On the development of B-Raf inhibitors acting through innovative mechanisms

Luca Pinzi

doi:10.12688/f1000research.108761.2

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Opinion Article

Revised

On the development of B-Raf inhibitors acting through innovative mechanisms

[version 2; peer review: 2 approved]

Luca Pinzi

PUBLISHED 26 Apr 2022

Author details Author details

Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

Luca Pinzi
Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Oncology gateway.

Abstract

B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Several studies have demonstrated that this protein is frequently upregulated in human cancers, especially when it bears activating mutations. In the last years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance.
Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good promises. However, several limitations could still be envisioned for these compounds, according to literature data. Besides, increased attentions have arisen around approaches based on the design of allosteric modulators, polypharmacology, proteolysis targeting chimeras (PROTACs) and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, current approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies.

Keywords

B-Raf, allosteric inhibitors, polypharmacology, drug repurposing, PROTACs, drug discovery and development, small molecule inhibitors.

Corresponding author: Luca Pinzi

Competing interests: No competing interests were disclosed.

Grant information: Luca Pinzi was supported by a FIRC-AIRC fellowship for Italy [rif. 24096].
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2022 Pinzi L. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Pinzi L. On the development of B-Raf inhibitors acting through innovative mechanisms [version 2; peer review: 2 approved]. F1000Research 2022, 11:237 (https://doi.org/10.12688/f1000research.108761.2) First published: 25 Feb 2022, 11:237 (https://doi.org/10.12688/f1000research.108761.1) Latest published: 26 Apr 2022, 11:237 (https://doi.org/10.12688/f1000research.108761.2)

Revised Amendments from Version 1

In response to the Reviewers’ very helpful suggestions, I made the following amendments to the manuscript. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect to ATP-competitive inhibitors. Moreover, a description on the main elements characterizing the ATP-binding site of the kinases was also reported. This allowed also to better: (i) highlight how Ponatinib and PHI1 can be classified according to their experimentally derived binding mode, and; (ii) contextualize their example with respect to the type III B-Raf allosteric pocket mentioned within the manuscript. Moreover, the text was also revised to include additional insights on some of the experimental and in silico approaches that are expected to be of help for kinase allosteric drug design. A discussion on the main challenges that might be faced when rationally designing multi-kinase inhibitors was provided. Moreover, the main E3 ligases exploited so far for the design of PROTACs are also now listed, along with their full name. The text was carefully revised to remove typos and to improve its readability, while additional references to relevant literature data were also added in support of the revisions. The full name of the reported abbreviations was added where needed, in agreement to the Reviewers’ comments. Finally, Figure 1 was revised to remove typos and to improve the image contents, as suggested.

See the author's detailed response to the review by Andrew Anighoro
See the author's detailed response to the review by Federico Falchi

Data availability

No data are associated with this article.

Author contributions

L.P.: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing.

Acknowledgments

The author is pleased to acknowledge Professor Giulio Rastelli (University of Modena and Reggio Emilia) for the helpful advices and fruitful discussion.

References

1. Dienstmann R, Tabernero J: BRAF as a Target for Cancer Therapy. Anti Cancer Agents Med. Chem. 2011; 11(3): 285–295. Publisher Full Text
2. Karasarides M, Chiloeches A, Hayward R, et al.: B-RAF is a therapeutic target in melanoma. Oncogene 2004; 23(37): 6292–6298. Publisher Full Text
3. Wellbrock C, Karasarides M, Marais R: The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 2004; 5(11): 875–885. PubMed Abstract | Publisher Full Text
4. Steelman LS, Pohnert SC, Shelton JG, et al.: JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 2004; 18(2): 189–218. PubMed Abstract | Publisher Full Text
5. Hilger RA, Scheulen ME, Strumberg D: The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer. Oncol. Res. Treat. 2002; 25(6): 511–518. Publisher Full Text
6. Garnett MJ, Marais R: Guilty as charged: B-RAF is a human oncogene. Cancer Cell 2004; 6(4): 313–319. Publisher Full Text
7. Zhang W, Liu HT: MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002; 12(1): 9–18. Publisher Full Text
8. Avruch J, Khokhlatchev A, Kyriakis JM, et al.: Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog. Horm. Res. 2001; 56: 127–156. PubMed Abstract | Publisher Full Text
9. Alqathama A: BRAF in malignant melanoma progression and metastasis: potentials and challenges. Am. J. Cancer Res. 2020; 10(4): 1103–1114.
10. Wan PTC, Garnett MJ, Roe SM, et al.: Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF. Cell 2004; 116(6): 855–867. PubMed Abstract | Publisher Full Text
11. McCubrey JA, Steelman LS, Chappell WH, et al.: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta 2007; 1773(8): 1263–1284. PubMed Abstract | Publisher Full Text
12. Zaman A, Wu W, Bivona TG: Targeting Oncogenic BRAF: Past, Present, and Future. Cancers. 2019; 11(8): 1197. PubMed Abstract | Publisher Full Text
13. Karoulia Z, Gavathiotis E, Poulikakos PI: New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 2017; 17(11): 676–691. PubMed Abstract | Publisher Full Text
14. Attwood MM, Fabbro D, Sokolov AV, et al.: Trends in kinase drug discovery: targets, indications and inhibitor design. Nat. Rev. Drug Discov. 2021; 20(11): 839–861.
15. Grassi E, Corbelli J, Papiani G, et al.: Current Therapeutic Strategies in BRAF-Mutant Metastatic Colorectal Cancer. Front. Oncol. 2021; 11: 601722. PubMed Abstract | Publisher Full Text
16. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011; 364(26): 2507–2516.
17. Villanueva J, Vultur A, Herlyn M: Resistance to BRAF Inhibitors: Unraveling Mechanisms and Future Treatment Options. Cancer Res. 2011; 71(23): 7137–7140. PubMed Abstract | Publisher Full Text
18. Shtivelman E, Davies MQA, Hwu P, et al.: Pathways and therapeutic targets in melanoma. Oncotarget 2014; 5(7): 1701–1752.
19. Manzano JL, Layos L, Bugés C, et al.: Resistant mechanisms to BRAF inhibitors in melanoma. Ann. Transl. Med. 2016; 4(12): 237. PubMed Abstract | Publisher Full Text
20. Yaeger R, Yao Z, Hyman DM, et al.: Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition. Cancer Res. 2017; 77(23): 6513–6523. PubMed Abstract | Publisher Full Text
21. Poulikakos PI, Zhang C, Bollag G, et al.: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464(7287): 427–430. PubMed Abstract | Publisher Full Text
22. Hatzivassiliou G, Song K, Yen I, et al.: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464(7287): 431–435. PubMed Abstract | Publisher Full Text
23. Anforth RM, Blumetti TCMP, Kefford RF, et al.: Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br. J. Dermatol. 2012; 167(5): 1153–1160. PubMed Abstract | Publisher Full Text
24. Lavoie H, Thevakumaran N, Gavory G, et al.: Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization. Nat. Chem. Biol. 2013; 9(7): 428–436. PubMed Abstract | Publisher Full Text
25. Anforth R, Fernandez-Peñas P, Long GV: Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013; 14(1): e11–e18. Publisher Full Text
26. Lacouture ME, Duvic M, Hauschild A, et al.: Analysis of dermatologic events in Vemurafenib-treated patients with melanoma. Oncologist 2013; 18(3): 314–322. PubMed Abstract | Publisher Full Text
27. Cichowski K, Jänne PA: Inhibitors that activate. Nature 2010; 464(7287): 358–359. Publisher Full Text
28. Agianian B, Gavathiotis E: Current insights of BRAF inhibitors in cancer. J. Med. Chem. 2018; 61(14): 5775–5793.
29. Jin T, Lavoie H, Sahmi M, et al.: RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition. Nat. Commun. 2017; 8(1): 1211. PubMed Abstract | Publisher Full Text
30. Liao JJ, Andrews RC:Targeting protein multiple conformations: a structure-based strategy for kinase drug design. Curr. Top. Med. Chem. 2007;7(14):1394–1407. PubMed Abstract | Publisher Full Text
31. Gagic Z, Ruzic D, Djokovic N, et al.:In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs. Front. Chem. 2020;7: 873. PubMed Abstract | Publisher Full Text
32. Aronov AM, Mc Clain B, Moody CS, et al.:Kinase-likeness and kinase-privileged fragments: toward virtual polypharmacology. J. Med. Chem. 2008;51(5):1214–1222. PubMed Abstract | Publisher Full Text
33. Yao Z, Torres NM, Tao A, et al.: BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell. 2015; 28(3): 370–383.
34. Karoulia Z, Wu Y, Ahmed TA, et al.: An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. Cancer Cell 2016; 30(3): 485–498. PubMed Abstract | Publisher Full Text
35. Okaniwa M, Hirose M, Arita T, et al.: Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives. J. Med. Chem. 2013; 56(16): 6478–6494.
36. Henry JR, Kaufman MD, Peng S-B, et al.: Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl) urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells. J. Med. Chem. 2015; 58(10): 4165–4179. PubMed Abstract | Publisher Full Text
37. Girotti MR, Lopes F, Preece N, et al.: Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma. Cancer Cell 2015; 27(1): 85–96. PubMed Abstract | Publisher Full Text
38. Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr. Opin. Oncol. 2018; 30(2): 125–133.
39. Zhang C, Spevak W, Zhang Y, et al.: RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 2015; 526(7574): 583–586. PubMed Abstract | Publisher Full Text
40. Wichmann J, Rynn C, Friess T, et al.: Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor. Clin. Cancer Res. 2021. PubMed Abstract | Publisher Full Text
41. Cook FA, Cook SJ: Inhibition of RAF dimers: it takes two to tango. Biochem. Soc. Trans. 2020; 49(1): 237–251.
42. Bhullar KS, Lagarón NO, McGowan EM, et al.: Kinase-targeted cancer therapies: progress, challenges and future directions. Mol. Cancer 2018; 17(1): 48. PubMed Abstract | Publisher Full Text
43. Martinez Fiesco JA, Durrant DE, Morrison DK, et al.:Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding. Nat. Commun. 2022;13: 486. Publisher Full Text
44. Shoemaker SC, Ando N:X-rays in the Cryo-Electron Microscopy Era: Structural Biology's Dynamic Future. Biochemistry. 2018;57(3):277–285. PubMed Abstract | Publisher Full Text
45. Tunyasuvunakool K, Adler J, Wu Z, et al.:Highly accurate protein structure prediction for the human proteome. Nature. 2021;596:590–596. PubMed Abstract | Publisher Full Text
46. Maloney RC, Zhang M, Jang H, et al.:The mechanism of activation of monomeric B-Raf V600E. Comput. Struct. Biotechnol. J. 2021;19:3349–3363. PubMed Abstract | Publisher Full Text
47. Yueh C, Rettenmaier J, Xia B, et al.:Kinase Atlas: Druggability Analysis of Potential Allosteric Sites in Kinases. J. Med. Chem. 2019;62(14):6512–6524. PubMed Abstract | Publisher Full Text
48. Lu X, Smaill JB, Ding K: New Promise and Opportunities for Allosteric Kinase Inhibitors. Angew. Chem. Int. Ed. Engl. 2020; 59(33): 13764–13776. PubMed Abstract | Publisher Full Text
49. Wu P, Clausen MH, Nielsen TE: Allosteric small-molecule kinase inhibitors. Pharmacol. Ther. 2015; 156: 59–68. Publisher Full Text
50. Beneker CM, Rovoli M, Kontopidis G, et al.: Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation. J. Med. Chem. 2019; 62(8): 3886–3897. PubMed Abstract | Publisher Full Text
51. Gunderwala AY, Nimbvikar AA, Cope NJ, et al.: Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF. ACS Chem. Biol. 2019; 14(7): 1471–1480. PubMed Abstract | Publisher Full Text
52. Maity S, Pai KSR, Nayak Y: Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance. Pharmacol. Rep. 2020; 72(4): 799–813.
53. Carlino L, Christodoulou MS, Restelli V, et al.: Structure–Activity Relationships of Hexahydrocyclopenta [c] quinoline Derivatives as Allosteric Inhibitors of CDK2 and EGFR. ChemMedChem 2018; 13(24): 2627–2634. PubMed Abstract | Publisher Full Text
54. Caporuscio F, Tinivella A, Restelli V, et al.: Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking. Fut. Med. Chem. 2018; 10(13): 1545–1553. PubMed Abstract | Publisher Full Text
55. Hindie V, Stroba A, Zhang H, et al.: Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat. Chem. Biol. 2009; 5(10): 758–764. PubMed Abstract | Publisher Full Text
56. Rice KD, Aay N, Anand NK, et al.: Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med. Chem. Lett. 2012; 3(5): 416–421. PubMed Abstract | Publisher Full Text
57. Hatzivassiliou G, Haling JR, Chen H, et al.: Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 2013; 501(7466): 232–236. PubMed Abstract | Publisher Full Text
58. Jia Y, Yun C-H, Park E, et al.: Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016; 534(7605): 129–132. PubMed Abstract | Publisher Full Text
59. To C, Jang J, Chen T, et al.: Single and dual targeting of mutant EGFR with an allosteric inhibitor. Cancer Discov. 2019; 9(7): 926–943. PubMed Abstract | Publisher Full Text
60. Khan ZM, Real AM, Marsiglia WM, et al.: Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature 2020; 588(7838): 509–514. PubMed Abstract | Publisher Full Text
61. Rastelli G, Anighoro A, Chripkova M, et al.: Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2. Cell Cycle 2014; 13(14): 2296–2305. PubMed Abstract | Publisher Full Text
62. Sturm N, Tinivella A, Rastelli G: Exploration and comparison of the geometrical and physicochemical properties of an αc allosteric pocket in the structural kinome. J. Chem. Inf. Model. 2018; 58(5): 1094–1103. PubMed Abstract | Publisher Full Text
63. Cotto-Rios XM, Agianian B, Gitego N, et al.: Inhibitors of BRAF dimers using an allosteric site. Nat. Commun. 2020; 11(1): 4370. PubMed Abstract | Publisher Full Text
64. Li Y, Guo B, Xu Z, et al.: Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay. Sci. Rep. 2016; 6(1): 31074. PubMed Abstract | Publisher Full Text
65. Pushpakom S, Iorio F, Eyers PA, et al.: Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019; 18(1): 41–58. PubMed Abstract | Publisher Full Text
66. Rastelli G, Pellati F, Pinzi L, et al.: Repositioning Natural Products in Drug Discovery. Molecules 2020; 25(5): 1154. PubMed Abstract | Publisher Full Text
67. Sleire L, Førde HE, Netland IA, et al.: Drug repurposing in cancer. Pharmacol. Res. 2017; 124: 74–91. Publisher Full Text
68. Farha MA, Brown ED: Drug repurposing for antimicrobial discovery. Nat. Microbiol. 2019; 4(4): 565–577. Publisher Full Text
69. Pinzi L, Lherbet C, Baltas M, et al.: In silico repositioning of Cannabigerol as a novel inhibitor of the Enoyl Acyl Carrier Protein (ACP) Reductase (InhA). Molecules 2019; 24(14): 2567. PubMed Abstract | Publisher Full Text
70. Brighenti V, Iseppi R, Pinzi L, et al.: Antifungal Activity and DNA Topoisomerase Inhibition of Hydrolysable Tannins from Punica granatum L. Int. J. Mol. Sci. 2021; 22(8): 4175. Publisher Full Text
71. Pinzi L, Tinivella A, Caporuscio F, et al.: Drug repurposing and polypharmacology to fight SARS-CoV-2 through inhibition of the Main Protease. Front. Pharmacol. 2021; 12: 636989. PubMed Abstract | Publisher Full Text
72. Freeman AK, Ritt DA, Morrison DK: Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. Mol. Cell 2013; 49(4): 751–758.
73. Cope NJ, Novak B, Liu Z, et al.: Analyses of the oncogenic BRAFD594G variant reveal a kinase-independent function of BRAF in activating MAPK signaling. J. Biol. Chem. 2020; 295(8): 2407–2420. PubMed Abstract | Publisher Full Text
74. Martinez R, Defnet A, Shapiro P: Avoiding or Co-Opting ATP Inhibition: overview of type III, IV, V, and VI Kinase Inhibitors. Shapiro P, editor. Next Generation Kinase Inhibitors: Moving Beyond the ATP Binding/Catalytic Sites Cham: Springer International Publishing; 2020; pp. 29–59.
75. Anighoro A, Bajorath J, Rastelli G: Polypharmacology: Challenges and Opportunities in Drug Discovery. J. Med. Chem. 2014; 57(19): 7874–7887. PubMed Abstract | Publisher Full Text
76. Rastelli G, Pinzi L: Computational polypharmacology comes of age. Front. Pharmacol. 2015; 6: 157.
77. Reddy AS, Zhang S: Polypharmacology: drug discovery for the future. Expert. Rev. Clin. Pharmacol. 2013; 6(1): 41–47. PubMed Abstract | Publisher Full Text
78. Bayat Mokhtari R, Homayouni TS, Baluch N, et al.: Combination therapy in combating cancer. Oncotarget 2017; 8(23): 38022–38043. PubMed Abstract | Publisher Full Text
79. Proietti I, Skroza N, Michelini S, et al.: BRAF inhibitors: molecular targeting and immunomodulatory actions. Cancers. 2020; 12(7): 1823. PubMed Abstract | Publisher Full Text
80. Robert C, Karaszewska B, Schachter J, et al.: Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N. Engl. J. Med. 2015; 372(1): 30–39.
81. Shi H, Hugo W, Kong X, et al.: Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014; 4(1): 80–93. PubMed Abstract | Publisher Full Text
82. Rizos H, Menzies AM, Pupo GM, et al.: BRAF inhibitor resistance mechanisms in metastatic Melanoma: spectrum and clinical impact. Clin. Cancer Res. 2014; 20(7): 1965–1977. PubMed Abstract | Publisher Full Text
83. Trepel J, Mollapour M, Giaccone G, et al.: Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer 2010; 10(8): 537–549. PubMed Abstract | Publisher Full Text
84. da Rocha DS , Friedlos F, Light Y, et al.: Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-Allylamino-17-Demethoxygeldanamycin. Cancer Res. 2005; 65(23): 10686–10691. Publisher Full Text
85. Paraiso KHT, Haarberg HE, Wood E, et al.: The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin. Cancer Res. 2012; 18(9): 2502–2514.
86. Smyth T, Paraiso KHT, Hearn K, et al.: Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in Melanoma models. Mol. Cancer Ther. 2014; 13(12): 2793–2804.
87. Smith DL, Acquaviva J, Sequeira M, et al.: The HSP90 inhibitor Ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer. Target. Oncol. 2015; 10(2): 235–245. PubMed Abstract | Publisher Full Text
88. Anighoro A, Pinzi L, Marverti G, et al.: Heat Shock Protein 90 and Serine/Threonine kinase B-Raf inhibitors have overlapping chemical space. RSC Adv. 2017; 7(49): 31069–31074. Publisher Full Text
89. Pinzi L, Foschi F, Christodoulou MS, et al.: Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity. ChemistryOpen. 2021; 10(12): 1177–1185. PubMed Abstract | Publisher Full Text
90. Cheng H, Chang Y, Zhang L, et al.: Identification and optimization of new dual inhibitors of B-Raf and Epidermal Growth Factor Receptor kinases for overcoming resistance against Vemurafenib. J. Med. Chem. 2014; 57(6): 2692–2703. PubMed Abstract | Publisher Full Text
91. Al-Wahaibi LH, Gouda AM, Abou-Ghadir OF, et al.: Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAFV600E dual inhibitors. Bioorg. Chem. 2020; 104: 104260. PubMed Abstract | Publisher Full Text
92. Abdel-Mohsen HT, Omar MA, El Kerdawy AM, et al.: Novel potent substituted 4-amino-2-thiopyrimidines as dual VEGFR-2 and BRAF kinase inhibitors. Eur. J. Med. Chem. 2019; 179: 707–722. PubMed Abstract | Publisher Full Text
93. Ali EMH, El-Telbany RFA, Abdel-Maksoud MS, et al.: Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors. Eur. J. Med. Chem. 2021; 215: 113277. PubMed Abstract | Publisher Full Text
94. Morphy R. Selectively nonselective kinase inhibition: striking the right balance. J. Med. Chem. 2010;53(4):1413–1437. PubMed Abstract | Publisher Full Text
95. Wang Y, Wan S, Li Z, et al.: Design, synthesis, biological evaluation and molecular modeling of novel 1H-pyrazolo[3,4-d] pyrimidine derivatives as BRAFV600E and VEGFR-2 dual inhibitors. Eur. J. Med. Chem. 2018; 155: 210–228. PubMed Abstract | Publisher Full Text
96. Okaniwa M, Hirose M, Imada T, et al.: Design and synthesis of novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds. J. Med. Chem. 2012; 55(7): 3452–3478. PubMed Abstract | Publisher Full Text
97. Alavi A, Hood JD, Frausto R, et al.: Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003; 301(5629): 94–96. PubMed Abstract | Publisher Full Text
98. Hood JD, Bednarski M, Frausto R, et al.: Tumor regression by targeted gene delivery to the neovasculature. Science 2002; 296(5577): 2404–2407. PubMed Abstract | Publisher Full Text
99. Youssif BGM, Gouda AM, Moustafa AH, et al.: Design and synthesis of new triarylimidazole derivatives as dual inhibitors of BRAFV600E/p38α with potential antiproliferative activity. J. Mol. Struct. 2022; 1253: 132218. Publisher Full Text
100. Yao YM, Donoho GP, Iversen PW, et al.: Mouse PDX trial suggests synergy of concurrent inhibition of RAF and EGFR in colorectal cancer with BRAF or KRAS mutations. Clin. Cancer Res. 2017; 23(18): 5547–5560. PubMed Abstract | Publisher Full Text
101. Oh S, Lim JH, Park N, et al.: Dual inhibition of EGFR and BRAF can be harmful in patients harboring an EGFR-activating mutation. J. Thorac. Oncol. 2020; 15(3): e32–e34. PubMed Abstract | Publisher Full Text
102. Pinzi L, Caporuscio F, Rastelli G: Selection of protein conformations for structure-based polypharmacology studies. Drug Discov. Today 2018; 23(11): 1889–1896. PubMed Abstract | Publisher Full Text
103. Pinzi L, Rastelli G: Molecular docking: shifting paradigms in drug discovery. Int. J. Mol. Sci. 2019; 20(18): 4331. PubMed Abstract | Publisher Full Text
104. Lai AC, Crews CM: Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 2017; 16(2): 101–114. PubMed Abstract | Publisher Full Text
105. Burslem GM, Crews CM: Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 2020; 181(1): 102–114. PubMed Abstract | Publisher Full Text
106. Sakamoto KM, Kim KB, Kumagai A, et al.: Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. U. S. A. 2001; 98(15): 8554–8559. PubMed Abstract | Publisher Full Text
107. Salami J, Crews CM: Waste disposal-An attractive strategy for cancer therapy. Science 2017; 355(6330): 1163–1167. Publisher Full Text
108. Posternak G, Tang X, Maisonneuve P, et al.: Functional characterization of a PROTAC directed against BRAF mutant V600E. Nat. Chem. Biol. 2020; 16(11): 1170–1178. PubMed Abstract | Publisher Full Text
109. Han X-R, Chen L, Wei Y, et al.: Discovery of selective small molecule degraders of BRAF-V600E. J. Med. Chem. 2020; 63(8): 4069–4080. PubMed Abstract | Publisher Full Text
110. Alabi S, Jaime-Figueroa S, Yao Z, et al.: Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 2021; 12(1): 920. PubMed Abstract | Publisher Full Text
111. He M, Lv W, Rao Y: Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation. Front. Cell Dev. Biol. 2021; 9: 685106. Publisher Full Text
112. Garuti L, Roberti M, Bottegoni G: Multi-kinase inhibitors. Curr. Med. Chem. 2015; 22(6): 695–712. Publisher Full Text
113. Proschak E, Stark H, Merk D: Polypharmacology by design: a medicinal chemist’s perspective on multitargeting compounds. J. Med. Chem. 2019; 62(2): 420–444. PubMed Abstract | Publisher Full Text

Schematic representation of the approaches currently pursued for the design of B-Raf ligands, discussed in the article.

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Version 2

VERSION 2 PUBLISHED 25 Feb 2022

Author details Author details

Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

Luca Pinzi
Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

Luca Pinzi was supported by a FIRC-AIRC fellowship for Italy [rif. 24096].
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Revised

Published: 26 Apr 2022, 11:237

https://doi.org/10.12688/f1000research.108761.2

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Published: 25 Feb 2022, 11:237

https://doi.org/10.12688/f1000research.108761.1

© 2022 Pinzi L. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Pinzi L. On the development of B-Raf inhibitors acting through innovative mechanisms [version 2; peer review: 2 approved] F1000Research 2022, 11:237 (https://doi.org/10.12688/f1000research.108761.2)

NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Key to Reviewer Statuses VIEW HIDE

ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions

Version 2

VERSION 2

PUBLISHED 26 Apr 2022

Revised

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Reviewer Report 26 Apr 2022

Andrew Anighoro, Relation Therapeutics LTD, London, UK

Approved

https://doi.org/10.5256/f1000research.132428.r135948

The author has appropriately and extensively addressed ... Continue reading

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Version 1

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PUBLISHED 25 Feb 2022

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Reviewer Report 15 Mar 2022

Andrew Anighoro, Relation Therapeutics LTD, London, UK

Approved with Reservations

https://doi.org/10.5256/f1000research.120182.r125513

The author gives an overview of B-Raf as a known target for cancer related diseases. Then, provides an account of design strategies that may overcome some limitations of typical ATP competitive drugs.

The author mostly refers

The author mostly refers to B-Raf as a target validated by "recent" evidence/studies, while it has been described in the literature as an oncogene at least from the 90s and Vemurafenib began clinical testing in 2008 to be approved in 2011 by FDA followed shortly by other drugs. I don't think this makes the article less interesting, but I feel that B-Raf should be referred sometimes in the text with adjectives such as "well established" rather than "recent".
Would it be possible to give the reader an idea of how the αC-helix is structurally related to the ATP binding site? Maybe through a sentence in the text and/or marking it in Figure 1?
When writing “activation loop”, “activation segment” and “αC-helix” are italics and quotes necessary? αC-helix has already been used several times in the text up until then without quotes or italics.
I think that the sentence "recent advancements in crystallographic and in silico techniques will certainly help to overcome several of the issues currently encountered in kinase allosteric ligand design" should be followed by at least mentioning some examples of techniques that the author is certain are going to help.
Can it be explained more explicitly why Ponatinib/PHI1 do not qualify as allosteric inhibitors?
Would it be possible to include a comment on the challenge of rationally designing kinase multitarget inhibitors given the selectivity issues mentioned by the author?
The first time that the term PROTAC is mentioned, it should be by the full name followed by the abbreviation, proteolysis targeting chimera (PROTAC).
"(e.g., an E3 ligase as VHL)" Probably, CRBN should be mentioned as well. Both should be mentioned by their full name first.
Probably, "e.g." in Figure 1 when addressing E3 ligases can be removed as it makes it look like E3 ligases can be replaced by something else in the context of PROTACs. I am not aware if that's actually possible, but if that's the case, it should be mentioned in the text.
In the abstract and in the main text the word premises is used a few times instead of promise, I believe.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Are arguments sufficiently supported by evidence from the published literature?

Yes
Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Drug discovery, computational chemistry.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 26 Apr 2022

Luca Pinzi, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

26 Apr 2022

Author Response

I would like to thank the Reviewer for the comments and the precious suggestions. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect ... Continue reading I would like to thank the Reviewer for the comments and the precious suggestions. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect to established efforts (e.g., ATP-competitive inhibitors development). Accordingly, the descriptions referring to literature data were also revised under a more contemporary perspective.

A brief description of the main elements characterizing the ATP-binding site of the kinases was reported in the revised version of the manuscript. This helped to delineate how the regulatory αC-helix is related to the other structural regions in the kinases ATP binding site. Besides, Figure 1 was also revised to better highlight the position of the αC-helix, with respect to the hinge region in the B-Raf active site to which ATP-competitive inhibitors bind to, and to improve the image contents.

The text was also revised to provide further insights on some of the experimental techniques and in silico approaches that are (and are also expected to be even more in the future) of help for kinase allosteric drug design efforts. Moreover, additional references to relevant literature data were included in the revised version of the manuscript to better contextualize the application of some of these techniques, on both B-Raf related research and a more general perspective.

An explanation of how Ponatinib and PHI1 can be classified according to their experimentally derived binding mode is now provided in the text, as suggested by the Reviewer. As revised, the text is expected to help better contextualize the example reported on Ponatinib/PHI1, with respect to the type III B-Raf allosteric pocket mentioned within this article.

The main challenges that might be faced when rationally designing multi-kinase inhibitors are now discussed in the text. Moreover, the main E3 ligases that have been exploited so far for the design of PROTACs are now reported within the text.

The manuscript was carefully revised, to remove typos and to make it clearer to readers. Moreover, the full names of the reported abbreviations were added within the text where needed.
I would like to thank the Reviewer for the comments and the precious suggestions. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect to established efforts (e.g., ATP-competitive inhibitors development). Accordingly, the descriptions referring to literature data were also revised under a more contemporary perspective.

A brief description of the main elements characterizing the ATP-binding site of the kinases was reported in the revised version of the manuscript. This helped to delineate how the regulatory αC-helix is related to the other structural regions in the kinases ATP binding site. Besides, Figure 1 was also revised to better highlight the position of the αC-helix, with respect to the hinge region in the B-Raf active site to which ATP-competitive inhibitors bind to, and to improve the image contents.

The text was also revised to provide further insights on some of the experimental techniques and in silico approaches that are (and are also expected to be even more in the future) of help for kinase allosteric drug design efforts. Moreover, additional references to relevant literature data were included in the revised version of the manuscript to better contextualize the application of some of these techniques, on both B-Raf related research and a more general perspective.

An explanation of how Ponatinib and PHI1 can be classified according to their experimentally derived binding mode is now provided in the text, as suggested by the Reviewer. As revised, the text is expected to help better contextualize the example reported on Ponatinib/PHI1, with respect to the type III B-Raf allosteric pocket mentioned within this article.

The main challenges that might be faced when rationally designing multi-kinase inhibitors are now discussed in the text. Moreover, the main E3 ligases that have been exploited so far for the design of PROTACs are now reported within the text.

The manuscript was carefully revised, to remove typos and to make it clearer to readers. Moreover, the full names of the reported abbreviations were added within the text where needed.
Competing Interests: No competing interests were disclosed. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 26 Apr 2022

Luca Pinzi, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

26 Apr 2022

Author Response

I would like to thank the Reviewer for the comments and the precious suggestions. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect ... Continue reading I would like to thank the Reviewer for the comments and the precious suggestions. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect to established efforts (e.g., ATP-competitive inhibitors development). Accordingly, the descriptions referring to literature data were also revised under a more contemporary perspective.

A brief description of the main elements characterizing the ATP-binding site of the kinases was reported in the revised version of the manuscript. This helped to delineate how the regulatory αC-helix is related to the other structural regions in the kinases ATP binding site. Besides, Figure 1 was also revised to better highlight the position of the αC-helix, with respect to the hinge region in the B-Raf active site to which ATP-competitive inhibitors bind to, and to improve the image contents.

The text was also revised to provide further insights on some of the experimental techniques and in silico approaches that are (and are also expected to be even more in the future) of help for kinase allosteric drug design efforts. Moreover, additional references to relevant literature data were included in the revised version of the manuscript to better contextualize the application of some of these techniques, on both B-Raf related research and a more general perspective.

An explanation of how Ponatinib and PHI1 can be classified according to their experimentally derived binding mode is now provided in the text, as suggested by the Reviewer. As revised, the text is expected to help better contextualize the example reported on Ponatinib/PHI1, with respect to the type III B-Raf allosteric pocket mentioned within this article.

The main challenges that might be faced when rationally designing multi-kinase inhibitors are now discussed in the text. Moreover, the main E3 ligases that have been exploited so far for the design of PROTACs are now reported within the text.

The manuscript was carefully revised, to remove typos and to make it clearer to readers. Moreover, the full names of the reported abbreviations were added within the text where needed.
I would like to thank the Reviewer for the comments and the precious suggestions. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect to established efforts (e.g., ATP-competitive inhibitors development). Accordingly, the descriptions referring to literature data were also revised under a more contemporary perspective.

A brief description of the main elements characterizing the ATP-binding site of the kinases was reported in the revised version of the manuscript. This helped to delineate how the regulatory αC-helix is related to the other structural regions in the kinases ATP binding site. Besides, Figure 1 was also revised to better highlight the position of the αC-helix, with respect to the hinge region in the B-Raf active site to which ATP-competitive inhibitors bind to, and to improve the image contents.

The text was also revised to provide further insights on some of the experimental techniques and in silico approaches that are (and are also expected to be even more in the future) of help for kinase allosteric drug design efforts. Moreover, additional references to relevant literature data were included in the revised version of the manuscript to better contextualize the application of some of these techniques, on both B-Raf related research and a more general perspective.

An explanation of how Ponatinib and PHI1 can be classified according to their experimentally derived binding mode is now provided in the text, as suggested by the Reviewer. As revised, the text is expected to help better contextualize the example reported on Ponatinib/PHI1, with respect to the type III B-Raf allosteric pocket mentioned within this article.

The main challenges that might be faced when rationally designing multi-kinase inhibitors are now discussed in the text. Moreover, the main E3 ligases that have been exploited so far for the design of PROTACs are now reported within the text.

The manuscript was carefully revised, to remove typos and to make it clearer to readers. Moreover, the full names of the reported abbreviations were added within the text where needed.
Competing Interests: No competing interests were disclosed. Close
Report a concern

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Reviewer Report 04 Mar 2022

Federico Falchi, Laboratory of Computational Medicinal Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

Approved

https://doi.org/10.5256/f1000research.120182.r125510

In this nice perspective, Pinzi summarizes the current state-of-the-art in the development of B-Raf inhibitors acting through innovative mechanisms. After a brief introduction about the traditional inhibitors (Atp-competitive) with their big limitations, Pinzi describes the most challenging approaches such as the design of allosteric modulators, the polypharmacology, and the PROTACs design with an eye to the computational strategies.

The manuscript is well understandable, offering both a biological and medicinal chemistry point of view. The references are adequate.
I do believe that work can be accepted certainly for indexing.

I have only a very few minor remarks:

The sentence below is too long:

Besides, other studies have been focused on the development of compounds as PLX7904 and PLX8394, able to escape paradoxical activation of B-Raf (i.e., the so-called “paradox breakers”) and to overcome some of known resistance mechanisms associated to previously reported Raf inhibitors,36,37 the latter ligand currently being evaluated in Phase I/IIa clinical trials (ClinicalTrials.gov identifier: NCT02428712).

Please change for example as:

Besides, other studies have been focused on the development of compounds such as PLX7904 and PLX8394, able to escape paradoxical activation of B-Raf (i.e., the so-called “paradox breakers”) and to overcome some of the known resistance mechanisms associated with previously reported Raf inhibitors.

PLX8394 is currently being evaluated in Phase I/IIa clinical trials (ClinicalTrials.gov identifier: NCT02428712).
The sentence below is too long:

Nevertheless, the results prospected in this study paved the way towards the identification of innovative B-Raf inhibitors among approved drugs (i.e., drug repurposing) (Figure 1), this approach being already navigated also with natural products and clinically safe candidates, on different medicinal chemistry research areas

Please change for example as:

Nevertheless, the results prospected in this study paved the way towards the identification of innovative B-Raf inhibitors among approved drugs (i.e., drug repurposing) (Figure 1). This approach is already been conducted also with natural products and clinically safe candidates in different medicinal chemistry research areas.
The abbreviation NSCLC is not straightforward, the first time an abbreviation is used it should be explained.
In the image:
- a B in B-RAF is missing
- the bullets points are not all the same
- sometimes a period is used at the end of the sentence, other times not

Is the topic of the opinion article discussed accurately in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Are arguments sufficiently supported by evidence from the published literature?

Yes
Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Drug design and drug development by means of computational techniques.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Author Response 26 Apr 2022

Luca Pinzi, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

26 Apr 2022

Author Response

I would like to thank the Reviewer for their precious comments. The manuscript was carefully revised, and long sentences split to make the text clearer to readers, in agreement to ... Continue reading I would like to thank the Reviewer for their precious comments. The manuscript was carefully revised, and long sentences split to make the text clearer to readers, in agreement to the Reviewer suggestions. Moreover, the full name of the reported abbreviations was added in the text. Figure 1 was revised to remove typos as suggested and to improve the image contents.
I would like to thank the Reviewer for their precious comments. The manuscript was carefully revised, and long sentences split to make the text clearer to readers, in agreement to the Reviewer suggestions. Moreover, the full name of the reported abbreviations was added in the text. Figure 1 was revised to remove typos as suggested and to improve the image contents.
Competing Interests: No competing interests were disclosed. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 26 Apr 2022

Luca Pinzi, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

26 Apr 2022

Author Response

I would like to thank the Reviewer for their precious comments. The manuscript was carefully revised, and long sentences split to make the text clearer to readers, in agreement to ... Continue reading I would like to thank the Reviewer for their precious comments. The manuscript was carefully revised, and long sentences split to make the text clearer to readers, in agreement to the Reviewer suggestions. Moreover, the full name of the reported abbreviations was added in the text. Figure 1 was revised to remove typos as suggested and to improve the image contents.
I would like to thank the Reviewer for their precious comments. The manuscript was carefully revised, and long sentences split to make the text clearer to readers, in agreement to the Reviewer suggestions. Moreover, the full name of the reported abbreviations was added in the text. Figure 1 was revised to remove typos as suggested and to improve the image contents.
Competing Interests: No competing interests were disclosed. Close
Report a concern

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Version 2

VERSION 2 PUBLISHED 25 Feb 2022

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	1	2
Version 2 (revision) 26 Apr 22		read
Version 1 25 Feb 22	read	read

Federico Falchi, University of Bologna, Bologna, Italy
Andrew Anighoro, Relation Therapeutics LTD, London, UK

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Reviewer Report

5 Views

26 Apr 2022 | for Version 2

Andrew Anighoro, Relation Therapeutics LTD, London, UK

5 Views Cite this report Responses(0)

Approved

The author has appropriately and extensively addressed my previous review. I have no further comments.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Drug discovery, computational chemistry.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

17 Views

15 Mar 2022 | for Version 1

Andrew Anighoro, Relation Therapeutics LTD, London, UK

17 Views Cite this report Responses(1)

Approved With Reservations

The author mostly refers to B-Raf as a target validated by "recent" evidence/studies, while it has been described in the literature as an oncogene at least from the 90s and Vemurafenib began clinical testing in 2008 to be approved in 2011 by FDA followed shortly by other drugs. I don't think this makes the article less interesting, but I feel that B-Raf should be referred sometimes in the text with adjectives such as "well established" rather than "recent".
Would it be possible to give the reader an idea of how the αC-helix is structurally related to the ATP binding site? Maybe through a sentence in the text and/or marking it in Figure 1?
When writing “activation loop”, “activation segment” and “αC-helix” are italics and quotes necessary? αC-helix has already been used several times in the text up until then without quotes or italics.
I think that the sentence "recent advancements in crystallographic and in silico techniques will certainly help to overcome several of the issues currently encountered in kinase allosteric ligand design" should be followed by at least mentioning some examples of techniques that the author is certain are going to help.
Can it be explained more explicitly why Ponatinib/PHI1 do not qualify as allosteric inhibitors?
Would it be possible to include a comment on the challenge of rationally designing kinase multitarget inhibitors given the selectivity issues mentioned by the author?
The first time that the term PROTAC is mentioned, it should be by the full name followed by the abbreviation, proteolysis targeting chimera (PROTAC).
"(e.g., an E3 ligase as VHL)" Probably, CRBN should be mentioned as well. Both should be mentioned by their full name first.
Probably, "e.g." in Figure 1 when addressing E3 ligases can be removed as it makes it look like E3 ligases can be replaced by something else in the context of PROTACs. I am not aware if that's actually possible, but if that's the case, it should be mentioned in the text.
In the abstract and in the main text the word premises is used a few times instead of promise, I believe.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Are arguments sufficiently supported by evidence from the published literature?

Yes
Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Drug discovery, computational chemistry.

Respond to this report

Responses (1)

Author Response

26 Apr 2022

Luca Pinzi, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

I would like to thank the Reviewer for the comments and the precious suggestions. The manuscript was revised to better contextualize the development of innovative B-Raf targeting approaches, with respect to established efforts (e.g., ATP-competitive inhibitors development). Accordingly, the descriptions referring to literature data were also revised under a more contemporary perspective.

A brief description of the main elements characterizing the ATP-binding site of the kinases was reported in the revised version of the manuscript. This helped to delineate how the regulatory αC-helix is related to the other structural regions in the kinases ATP binding site. Besides, Figure 1 was also revised to better highlight the position of the αC-helix, with respect to the hinge region in the B-Raf active site to which ATP-competitive inhibitors bind to, and to improve the image contents.

The text was also revised to provide further insights on some of the experimental techniques and in silico approaches that are (and are also expected to be even more in the future) of help for kinase allosteric drug design efforts. Moreover, additional references to relevant literature data were included in the revised version of the manuscript to better contextualize the application of some of these techniques, on both B-Raf related research and a more general perspective.

An explanation of how Ponatinib and PHI1 can be classified according to their experimentally derived binding mode is now provided in the text, as suggested by the Reviewer. As revised, the text is expected to help better contextualize the example reported on Ponatinib/PHI1, with respect to the type III B-Raf allosteric pocket mentioned within this article.

The main challenges that might be faced when rationally designing multi-kinase inhibitors are now discussed in the text. Moreover, the main E3 ligases that have been exploited so far for the design of PROTACs are now reported within the text.

The manuscript was carefully revised, to remove typos and to make it clearer to readers. Moreover, the full names of the reported abbreviations were added within the text where needed.

View more View less

Competing Interests

No competing interests were disclosed.

Back to all reports

Reviewer Report

16 Views

04 Mar 2022 | for Version 1

Federico Falchi, Laboratory of Computational Medicinal Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

16 Views Cite this report Responses(1)

Approved

The sentence below is too long:

Besides, other studies have been focused on the development of compounds as PLX7904 and PLX8394, able to escape paradoxical activation of B-Raf (i.e., the so-called “paradox breakers”) and to overcome some of known resistance mechanisms associated to previously reported Raf inhibitors,36,37 the latter ligand currently being evaluated in Phase I/IIa clinical trials (ClinicalTrials.gov identifier: NCT02428712).

Please change for example as:

Besides, other studies have been focused on the development of compounds such as PLX7904 and PLX8394, able to escape paradoxical activation of B-Raf (i.e., the so-called “paradox breakers”) and to overcome some of the known resistance mechanisms associated with previously reported Raf inhibitors.

PLX8394 is currently being evaluated in Phase I/IIa clinical trials (ClinicalTrials.gov identifier: NCT02428712).
The sentence below is too long:

Nevertheless, the results prospected in this study paved the way towards the identification of innovative B-Raf inhibitors among approved drugs (i.e., drug repurposing) (Figure 1), this approach being already navigated also with natural products and clinically safe candidates, on different medicinal chemistry research areas

Please change for example as:

Nevertheless, the results prospected in this study paved the way towards the identification of innovative B-Raf inhibitors among approved drugs (i.e., drug repurposing) (Figure 1). This approach is already been conducted also with natural products and clinically safe candidates in different medicinal chemistry research areas.
The abbreviation NSCLC is not straightforward, the first time an abbreviation is used it should be explained.
In the image:
- a B in B-RAF is missing
- the bullets points are not all the same
- sometimes a period is used at the end of the sentence, other times not

Is the topic of the opinion article discussed accurately in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Are arguments sufficiently supported by evidence from the published literature?

Yes
Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Drug design and drug development by means of computational techniques.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (1)

Author Response

26 Apr 2022

Luca Pinzi, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

I would like to thank the Reviewer for their precious comments. The manuscript was carefully revised, and long sentences split to make the text clearer to readers, in agreement to the Reviewer suggestions. Moreover, the full name of the reported abbreviations was added in the text. Figure 1 was revised to remove typos as suggested and to improve the image contents.

View more View less

Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

[1] 1. Dienstmann R, Tabernero J: BRAF as a Target for Cancer Therapy. Anti Cancer Agents Med. Chem. 2011; 11(3): 285–295. Publisher Full Text

[2] 2. Karasarides M, Chiloeches A, Hayward R, et al.: B-RAF is a therapeutic target in melanoma. Oncogene 2004; 23(37): 6292–6298. Publisher Full Text

[3] 3. Wellbrock C, Karasarides M, Marais R: The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 2004; 5(11): 875–885. PubMed Abstract | Publisher Full Text

[4] 4. Steelman LS, Pohnert SC, Shelton JG, et al.: JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 2004; 18(2): 189–218. PubMed Abstract | Publisher Full Text

[5] 5. Hilger RA, Scheulen ME, Strumberg D: The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer. Oncol. Res. Treat. 2002; 25(6): 511–518. Publisher Full Text

[6] 6. Garnett MJ, Marais R: Guilty as charged: B-RAF is a human oncogene. Cancer Cell 2004; 6(4): 313–319. Publisher Full Text

[7] 7. Zhang W, Liu HT: MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002; 12(1): 9–18. Publisher Full Text

[8] 8. Avruch J, Khokhlatchev A, Kyriakis JM, et al.: Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog. Horm. Res. 2001; 56: 127–156. PubMed Abstract | Publisher Full Text

[9] 9. Alqathama A: BRAF in malignant melanoma progression and metastasis: potentials and challenges. Am. J. Cancer Res. 2020; 10(4): 1103–1114.

[10] 10. Wan PTC, Garnett MJ, Roe SM, et al.: Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF. Cell 2004; 116(6): 855–867. PubMed Abstract | Publisher Full Text

[11] 11. McCubrey JA, Steelman LS, Chappell WH, et al.: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta 2007; 1773(8): 1263–1284. PubMed Abstract | Publisher Full Text

[12] 12. Zaman A, Wu W, Bivona TG: Targeting Oncogenic BRAF: Past, Present, and Future. Cancers. 2019; 11(8): 1197. PubMed Abstract | Publisher Full Text

[13] 13. Karoulia Z, Gavathiotis E, Poulikakos PI: New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 2017; 17(11): 676–691. PubMed Abstract | Publisher Full Text

[14] 14. Attwood MM, Fabbro D, Sokolov AV, et al.: Trends in kinase drug discovery: targets, indications and inhibitor design. Nat. Rev. Drug Discov. 2021; 20(11): 839–861.

[15] 15. Grassi E, Corbelli J, Papiani G, et al.: Current Therapeutic Strategies in BRAF-Mutant Metastatic Colorectal Cancer. Front. Oncol. 2021; 11: 601722. PubMed Abstract | Publisher Full Text

[16] 16. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011; 364(26): 2507–2516.

[17] 17. Villanueva J, Vultur A, Herlyn M: Resistance to BRAF Inhibitors: Unraveling Mechanisms and Future Treatment Options. Cancer Res. 2011; 71(23): 7137–7140. PubMed Abstract | Publisher Full Text

[18] 18. Shtivelman E, Davies MQA, Hwu P, et al.: Pathways and therapeutic targets in melanoma. Oncotarget 2014; 5(7): 1701–1752.

[19] 19. Manzano JL, Layos L, Bugés C, et al.: Resistant mechanisms to BRAF inhibitors in melanoma. Ann. Transl. Med. 2016; 4(12): 237. PubMed Abstract | Publisher Full Text

[20] 20. Yaeger R, Yao Z, Hyman DM, et al.: Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition. Cancer Res. 2017; 77(23): 6513–6523. PubMed Abstract | Publisher Full Text

[21] 21. Poulikakos PI, Zhang C, Bollag G, et al.: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464(7287): 427–430. PubMed Abstract | Publisher Full Text

[22] 22. Hatzivassiliou G, Song K, Yen I, et al.: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464(7287): 431–435. PubMed Abstract | Publisher Full Text

[23] 23. Anforth RM, Blumetti TCMP, Kefford RF, et al.: Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br. J. Dermatol. 2012; 167(5): 1153–1160. PubMed Abstract | Publisher Full Text

[24] 24. Lavoie H, Thevakumaran N, Gavory G, et al.: Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization. Nat. Chem. Biol. 2013; 9(7): 428–436. PubMed Abstract | Publisher Full Text

[25] 25. Anforth R, Fernandez-Peñas P, Long GV: Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013; 14(1): e11–e18. Publisher Full Text

[26] 26. Lacouture ME, Duvic M, Hauschild A, et al.: Analysis of dermatologic events in Vemurafenib-treated patients with melanoma. Oncologist 2013; 18(3): 314–322. PubMed Abstract | Publisher Full Text

[27] 27. Cichowski K, Jänne PA: Inhibitors that activate. Nature 2010; 464(7287): 358–359. Publisher Full Text

[28] 28. Agianian B, Gavathiotis E: Current insights of BRAF inhibitors in cancer. J. Med. Chem. 2018; 61(14): 5775–5793.

[29] 29. Jin T, Lavoie H, Sahmi M, et al.: RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition. Nat. Commun. 2017; 8(1): 1211. PubMed Abstract | Publisher Full Text

[30] 30. Liao JJ, Andrews RC:Targeting protein multiple conformations: a structure-based strategy for kinase drug design. Curr. Top. Med. Chem. 2007;7(14):1394–1407. PubMed Abstract | Publisher Full Text

[31] 31. Gagic Z, Ruzic D, Djokovic N, et al.:In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs. Front. Chem. 2020;7: 873. PubMed Abstract | Publisher Full Text

[32] 32. Aronov AM, Mc Clain B, Moody CS, et al.:Kinase-likeness and kinase-privileged fragments: toward virtual polypharmacology. J. Med. Chem. 2008;51(5):1214–1222. PubMed Abstract | Publisher Full Text

[33] 33. Yao Z, Torres NM, Tao A, et al.: BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell. 2015; 28(3): 370–383.

[34] 34. Karoulia Z, Wu Y, Ahmed TA, et al.: An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. Cancer Cell 2016; 30(3): 485–498. PubMed Abstract | Publisher Full Text

[35] 35. Okaniwa M, Hirose M, Arita T, et al.: Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives. J. Med. Chem. 2013; 56(16): 6478–6494.

[36] 36. Henry JR, Kaufman MD, Peng S-B, et al.: Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl) urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells. J. Med. Chem. 2015; 58(10): 4165–4179. PubMed Abstract | Publisher Full Text

[37] 37. Girotti MR, Lopes F, Preece N, et al.: Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma. Cancer Cell 2015; 27(1): 85–96. PubMed Abstract | Publisher Full Text

[38] 38. Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr. Opin. Oncol. 2018; 30(2): 125–133.

[39] 39. Zhang C, Spevak W, Zhang Y, et al.: RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 2015; 526(7574): 583–586. PubMed Abstract | Publisher Full Text

[40] 40. Wichmann J, Rynn C, Friess T, et al.: Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor. Clin. Cancer Res. 2021. PubMed Abstract | Publisher Full Text

[41] 41. Cook FA, Cook SJ: Inhibition of RAF dimers: it takes two to tango. Biochem. Soc. Trans. 2020; 49(1): 237–251.

[42] 42. Bhullar KS, Lagarón NO, McGowan EM, et al.: Kinase-targeted cancer therapies: progress, challenges and future directions. Mol. Cancer 2018; 17(1): 48. PubMed Abstract | Publisher Full Text

[43] 43. Martinez Fiesco JA, Durrant DE, Morrison DK, et al.:Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding. Nat. Commun. 2022;13: 486. Publisher Full Text

[44] 44. Shoemaker SC, Ando N:X-rays in the Cryo-Electron Microscopy Era: Structural Biology's Dynamic Future. Biochemistry. 2018;57(3):277–285. PubMed Abstract | Publisher Full Text

[45] 45. Tunyasuvunakool K, Adler J, Wu Z, et al.:Highly accurate protein structure prediction for the human proteome. Nature. 2021;596:590–596. PubMed Abstract | Publisher Full Text

[46] 46. Maloney RC, Zhang M, Jang H, et al.:The mechanism of activation of monomeric B-Raf V600E. Comput. Struct. Biotechnol. J. 2021;19:3349–3363. PubMed Abstract | Publisher Full Text

[47] 47. Yueh C, Rettenmaier J, Xia B, et al.:Kinase Atlas: Druggability Analysis of Potential Allosteric Sites in Kinases. J. Med. Chem. 2019;62(14):6512–6524. PubMed Abstract | Publisher Full Text

[48] 48. Lu X, Smaill JB, Ding K: New Promise and Opportunities for Allosteric Kinase Inhibitors. Angew. Chem. Int. Ed. Engl. 2020; 59(33): 13764–13776. PubMed Abstract | Publisher Full Text

[49] 49. Wu P, Clausen MH, Nielsen TE: Allosteric small-molecule kinase inhibitors. Pharmacol. Ther. 2015; 156: 59–68. Publisher Full Text

[50] 50. Beneker CM, Rovoli M, Kontopidis G, et al.: Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation. J. Med. Chem. 2019; 62(8): 3886–3897. PubMed Abstract | Publisher Full Text

[51] 51. Gunderwala AY, Nimbvikar AA, Cope NJ, et al.: Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF. ACS Chem. Biol. 2019; 14(7): 1471–1480. PubMed Abstract | Publisher Full Text

[52] 52. Maity S, Pai KSR, Nayak Y: Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance. Pharmacol. Rep. 2020; 72(4): 799–813.

[53] 53. Carlino L, Christodoulou MS, Restelli V, et al.: Structure–Activity Relationships of Hexahydrocyclopenta [c] quinoline Derivatives as Allosteric Inhibitors of CDK2 and EGFR. ChemMedChem 2018; 13(24): 2627–2634. PubMed Abstract | Publisher Full Text

[54] 54. Caporuscio F, Tinivella A, Restelli V, et al.: Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking. Fut. Med. Chem. 2018; 10(13): 1545–1553. PubMed Abstract | Publisher Full Text

[55] 55. Hindie V, Stroba A, Zhang H, et al.: Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat. Chem. Biol. 2009; 5(10): 758–764. PubMed Abstract | Publisher Full Text

[56] 56. Rice KD, Aay N, Anand NK, et al.: Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med. Chem. Lett. 2012; 3(5): 416–421. PubMed Abstract | Publisher Full Text

[57] 57. Hatzivassiliou G, Haling JR, Chen H, et al.: Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 2013; 501(7466): 232–236. PubMed Abstract | Publisher Full Text

[58] 58. Jia Y, Yun C-H, Park E, et al.: Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016; 534(7605): 129–132. PubMed Abstract | Publisher Full Text

[59] 59. To C, Jang J, Chen T, et al.: Single and dual targeting of mutant EGFR with an allosteric inhibitor. Cancer Discov. 2019; 9(7): 926–943. PubMed Abstract | Publisher Full Text

[60] 60. Khan ZM, Real AM, Marsiglia WM, et al.: Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature 2020; 588(7838): 509–514. PubMed Abstract | Publisher Full Text

[61] 61. Rastelli G, Anighoro A, Chripkova M, et al.: Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2. Cell Cycle 2014; 13(14): 2296–2305. PubMed Abstract | Publisher Full Text

[62] 62. Sturm N, Tinivella A, Rastelli G: Exploration and comparison of the geometrical and physicochemical properties of an αc allosteric pocket in the structural kinome. J. Chem. Inf. Model. 2018; 58(5): 1094–1103. PubMed Abstract | Publisher Full Text

[63] 63. Cotto-Rios XM, Agianian B, Gitego N, et al.: Inhibitors of BRAF dimers using an allosteric site. Nat. Commun. 2020; 11(1): 4370. PubMed Abstract | Publisher Full Text

[64] 64. Li Y, Guo B, Xu Z, et al.: Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay. Sci. Rep. 2016; 6(1): 31074. PubMed Abstract | Publisher Full Text

[65] 65. Pushpakom S, Iorio F, Eyers PA, et al.: Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019; 18(1): 41–58. PubMed Abstract | Publisher Full Text

[66] 66. Rastelli G, Pellati F, Pinzi L, et al.: Repositioning Natural Products in Drug Discovery. Molecules 2020; 25(5): 1154. PubMed Abstract | Publisher Full Text

[67] 67. Sleire L, Førde HE, Netland IA, et al.: Drug repurposing in cancer. Pharmacol. Res. 2017; 124: 74–91. Publisher Full Text

[68] 68. Farha MA, Brown ED: Drug repurposing for antimicrobial discovery. Nat. Microbiol. 2019; 4(4): 565–577. Publisher Full Text

[69] 69. Pinzi L, Lherbet C, Baltas M, et al.: In silico repositioning of Cannabigerol as a novel inhibitor of the Enoyl Acyl Carrier Protein (ACP) Reductase (InhA). Molecules 2019; 24(14): 2567. PubMed Abstract | Publisher Full Text

[70] 70. Brighenti V, Iseppi R, Pinzi L, et al.: Antifungal Activity and DNA Topoisomerase Inhibition of Hydrolysable Tannins from Punica granatum L. Int. J. Mol. Sci. 2021; 22(8): 4175. Publisher Full Text

[71] 71. Pinzi L, Tinivella A, Caporuscio F, et al.: Drug repurposing and polypharmacology to fight SARS-CoV-2 through inhibition of the Main Protease. Front. Pharmacol. 2021; 12: 636989. PubMed Abstract | Publisher Full Text

[72] 72. Freeman AK, Ritt DA, Morrison DK: Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. Mol. Cell 2013; 49(4): 751–758.

[73] 73. Cope NJ, Novak B, Liu Z, et al.: Analyses of the oncogenic BRAFD594G variant reveal a kinase-independent function of BRAF in activating MAPK signaling. J. Biol. Chem. 2020; 295(8): 2407–2420. PubMed Abstract | Publisher Full Text

[74] 74. Martinez R, Defnet A, Shapiro P: Avoiding or Co-Opting ATP Inhibition: overview of type III, IV, V, and VI Kinase Inhibitors. Shapiro P, editor. Next Generation Kinase Inhibitors: Moving Beyond the ATP Binding/Catalytic Sites Cham: Springer International Publishing; 2020; pp. 29–59.

[75] 75. Anighoro A, Bajorath J, Rastelli G: Polypharmacology: Challenges and Opportunities in Drug Discovery. J. Med. Chem. 2014; 57(19): 7874–7887. PubMed Abstract | Publisher Full Text

[76] 76. Rastelli G, Pinzi L: Computational polypharmacology comes of age. Front. Pharmacol. 2015; 6: 157.

[77] 77. Reddy AS, Zhang S: Polypharmacology: drug discovery for the future. Expert. Rev. Clin. Pharmacol. 2013; 6(1): 41–47. PubMed Abstract | Publisher Full Text

[78] 78. Bayat Mokhtari R, Homayouni TS, Baluch N, et al.: Combination therapy in combating cancer. Oncotarget 2017; 8(23): 38022–38043. PubMed Abstract | Publisher Full Text

[79] 79. Proietti I, Skroza N, Michelini S, et al.: BRAF inhibitors: molecular targeting and immunomodulatory actions. Cancers. 2020; 12(7): 1823. PubMed Abstract | Publisher Full Text

[80] 80. Robert C, Karaszewska B, Schachter J, et al.: Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N. Engl. J. Med. 2015; 372(1): 30–39.

[81] 81. Shi H, Hugo W, Kong X, et al.: Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014; 4(1): 80–93. PubMed Abstract | Publisher Full Text

[82] 82. Rizos H, Menzies AM, Pupo GM, et al.: BRAF inhibitor resistance mechanisms in metastatic Melanoma: spectrum and clinical impact. Clin. Cancer Res. 2014; 20(7): 1965–1977. PubMed Abstract | Publisher Full Text

[83] 83. Trepel J, Mollapour M, Giaccone G, et al.: Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer 2010; 10(8): 537–549. PubMed Abstract | Publisher Full Text

[84] 84. da Rocha DS , Friedlos F, Light Y, et al.: Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-Allylamino-17-Demethoxygeldanamycin. Cancer Res. 2005; 65(23): 10686–10691. Publisher Full Text

[85] 85. Paraiso KHT, Haarberg HE, Wood E, et al.: The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin. Cancer Res. 2012; 18(9): 2502–2514.

[86] 86. Smyth T, Paraiso KHT, Hearn K, et al.: Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in Melanoma models. Mol. Cancer Ther. 2014; 13(12): 2793–2804.

[87] 87. Smith DL, Acquaviva J, Sequeira M, et al.: The HSP90 inhibitor Ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer. Target. Oncol. 2015; 10(2): 235–245. PubMed Abstract | Publisher Full Text

[88] 88. Anighoro A, Pinzi L, Marverti G, et al.: Heat Shock Protein 90 and Serine/Threonine kinase B-Raf inhibitors have overlapping chemical space. RSC Adv. 2017; 7(49): 31069–31074. Publisher Full Text

[89] 89. Pinzi L, Foschi F, Christodoulou MS, et al.: Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity. ChemistryOpen. 2021; 10(12): 1177–1185. PubMed Abstract | Publisher Full Text

[90] 90. Cheng H, Chang Y, Zhang L, et al.: Identification and optimization of new dual inhibitors of B-Raf and Epidermal Growth Factor Receptor kinases for overcoming resistance against Vemurafenib. J. Med. Chem. 2014; 57(6): 2692–2703. PubMed Abstract | Publisher Full Text

[91] 91. Al-Wahaibi LH, Gouda AM, Abou-Ghadir OF, et al.: Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAFV600E dual inhibitors. Bioorg. Chem. 2020; 104: 104260. PubMed Abstract | Publisher Full Text

[92] 92. Abdel-Mohsen HT, Omar MA, El Kerdawy AM, et al.: Novel potent substituted 4-amino-2-thiopyrimidines as dual VEGFR-2 and BRAF kinase inhibitors. Eur. J. Med. Chem. 2019; 179: 707–722. PubMed Abstract | Publisher Full Text

[93] 93. Ali EMH, El-Telbany RFA, Abdel-Maksoud MS, et al.: Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors. Eur. J. Med. Chem. 2021; 215: 113277. PubMed Abstract | Publisher Full Text

[94] 94. Morphy R. Selectively nonselective kinase inhibition: striking the right balance. J. Med. Chem. 2010;53(4):1413–1437. PubMed Abstract | Publisher Full Text

[95] 95. Wang Y, Wan S, Li Z, et al.: Design, synthesis, biological evaluation and molecular modeling of novel 1H-pyrazolo[3,4-d] pyrimidine derivatives as BRAFV600E and VEGFR-2 dual inhibitors. Eur. J. Med. Chem. 2018; 155: 210–228. PubMed Abstract | Publisher Full Text

[96] 96. Okaniwa M, Hirose M, Imada T, et al.: Design and synthesis of novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds. J. Med. Chem. 2012; 55(7): 3452–3478. PubMed Abstract | Publisher Full Text

[97] 97. Alavi A, Hood JD, Frausto R, et al.: Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003; 301(5629): 94–96. PubMed Abstract | Publisher Full Text

[98] 98. Hood JD, Bednarski M, Frausto R, et al.: Tumor regression by targeted gene delivery to the neovasculature. Science 2002; 296(5577): 2404–2407. PubMed Abstract | Publisher Full Text

[99] 99. Youssif BGM, Gouda AM, Moustafa AH, et al.: Design and synthesis of new triarylimidazole derivatives as dual inhibitors of BRAFV600E/p38α with potential antiproliferative activity. J. Mol. Struct. 2022; 1253: 132218. Publisher Full Text

[100] 100. Yao YM, Donoho GP, Iversen PW, et al.: Mouse PDX trial suggests synergy of concurrent inhibition of RAF and EGFR in colorectal cancer with BRAF or KRAS mutations. Clin. Cancer Res. 2017; 23(18): 5547–5560. PubMed Abstract | Publisher Full Text

[101] 101. Oh S, Lim JH, Park N, et al.: Dual inhibition of EGFR and BRAF can be harmful in patients harboring an EGFR-activating mutation. J. Thorac. Oncol. 2020; 15(3): e32–e34. PubMed Abstract | Publisher Full Text

[102] 102. Pinzi L, Caporuscio F, Rastelli G: Selection of protein conformations for structure-based polypharmacology studies. Drug Discov. Today 2018; 23(11): 1889–1896. PubMed Abstract | Publisher Full Text

[103] 103. Pinzi L, Rastelli G: Molecular docking: shifting paradigms in drug discovery. Int. J. Mol. Sci. 2019; 20(18): 4331. PubMed Abstract | Publisher Full Text

[104] 104. Lai AC, Crews CM: Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 2017; 16(2): 101–114. PubMed Abstract | Publisher Full Text

[105] 105. Burslem GM, Crews CM: Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 2020; 181(1): 102–114. PubMed Abstract | Publisher Full Text

[106] 106. Sakamoto KM, Kim KB, Kumagai A, et al.: Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. U. S. A. 2001; 98(15): 8554–8559. PubMed Abstract | Publisher Full Text

[107] 107. Salami J, Crews CM: Waste disposal-An attractive strategy for cancer therapy. Science 2017; 355(6330): 1163–1167. Publisher Full Text

[108] 108. Posternak G, Tang X, Maisonneuve P, et al.: Functional characterization of a PROTAC directed against BRAF mutant V600E. Nat. Chem. Biol. 2020; 16(11): 1170–1178. PubMed Abstract | Publisher Full Text

[109] 109. Han X-R, Chen L, Wei Y, et al.: Discovery of selective small molecule degraders of BRAF-V600E. J. Med. Chem. 2020; 63(8): 4069–4080. PubMed Abstract | Publisher Full Text

[110] 110. Alabi S, Jaime-Figueroa S, Yao Z, et al.: Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 2021; 12(1): 920. PubMed Abstract | Publisher Full Text

[111] 111. He M, Lv W, Rao Y: Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation. Front. Cell Dev. Biol. 2021; 9: 685106. Publisher Full Text

[112] 112. Garuti L, Roberti M, Bottegoni G: Multi-kinase inhibitors. Curr. Med. Chem. 2015; 22(6): 695–712. Publisher Full Text

[113] 113. Proschak E, Stark H, Merk D: Polypharmacology by design: a medicinal chemist’s perspective on multitargeting compounds. J. Med. Chem. 2019; 62(2): 420–444. PubMed Abstract | Publisher Full Text

On the development of B-Raf inhibitors acting through innovative mechanisms

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Schematic representation of the approaches currently pursued for the design of B-Raf ligands, discussed in the article.

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