Abstract
Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide. Through this effort, we obtained 6-chloro-5-((2,6-difluorophenyl)amino)-1H-indazole-4,7-dione (5i), which showed a highly potent activity with a half-maximal inhibitory concentration (IC50) of 60 nM. The in vivo xenograft assay confirmed that the 1H-indazol-4,7-dione compound reduced the tumor size significantly. These results show that the 1H-indazol-4,7-dione scaffold is highly potent against bromodomain.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, Iyer MK, Jing X, Wu YM, Cao X, Qin ZS, Wang S, Feng FY, Chinnaiyan AM (2014) Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510:247–282
Bouillez A, Rajabi H, Pitroda S, Jin C, Alam M, Kharbanda A, Tagde A, Wong KK, Kufe D (2016) Inhibition of MUC1-C suppresses myc expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas. Cancer Res 76:1538–1548
Coude MM, Braun T, Berrou J, Dupont M, Bertrand S, Masse A, Faffoux E, Itzykson R, Delord M, Riveiro ME, Herait P, Baruchel A, Dombret H, Gardin C (2015) Bet inhibitor OTX015 targts BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget 6:17698–17712
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–917
Devaiah BN, Case-Borden C, Gegonne A, Hsu CH, Chen Q, Meerzaman D, Dey A, Ozato K, Singer DS (2016) BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin. Nat Struct Mol Biol 23:540–548
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE (2010) Selective inhibition of BET bromodomains. Nature 468:1067–1073
Fong CY, Gilan O, Lam EYN, Rubin AF, Ftouni S, Tyler D, Stanley K, Sinha D, Yeh P, Morison J, Giotopoulos G, Lugo D, Jeffrey P, Lee SC-W, Carpenter C, Gregory R, Ramsay RG, Lane SW, Abdel-Wahab O, Kouzarides T, Johnstone RW, Dawson SJ, Huntly BJP, Prinjha RK, Papenfuss AT, Dawson MA (2015) BET inhibitor resistance emerges from leukaemia stem cells. Nature 525:538–542
French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, Thyne ME, Kutok JL, Toretsky JA, Tadavarthy AK, Kees UR, Fletcher JA, Aster JC (2008) BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27:2237–2242
Garnier JM, Sharp PP, Burns CJ (2014) BET bromodomain inhibitors: a patent review. Expert Opin Ther Pat 24:185–199
Jiang YW, Veschambre P, Erdjument-Bromage H, Tempst P, Conaway JW, Conaway RC, Kornberg RD (1998) Mammalian mediator of transcriptional regulation and its possible role as an endpoint of signal transduction pathways. Proc Natl Acad Sci USA 95:8538–8543
Jung M, Philpott M, Müller S, Schulze J, Badock V, Eberspächer U, Moosmayer D, Bader B, Schmees N, Fernández-Montalván A, Haendler B (2014) Affinity map of bromodomain protein 4 (BRD4) interactions with the histone H4 tail and the small molecule inhibitor JQ1. J Biol Chem 289:9304–9319
Korb E, Herre M, Zucker-Scharff I, Darnell RB, Allis CD (2015) BET protein Brd4 activates transcription in neurons and BET inhibitor JQ-1 blocks memory in mice. Nat Neurosci 18:1464–1473
Miller DM, Thomas SD, Islam A, Muench D, Sedoris K (2012) c-Myc and cancer metabolism. Clin Cancer Res 18:5546–5553
Mirguet O, Gosmini R, Toum J, Clement CA, Barnathan M, Brusq JM, Mordaunt JE, Grimes RM, Crowe M, Pineau O, Ajakane M, Daugan A, Jeffrey P, Cutler L, Haynes AC, Smithers NN, Chung CW, Bamborough P, Uings IJ, Lewis A, Witherington J, Parr N, Prinjha RK, Nicodeme E (2013) Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem 56:7501–7515
Müller S, Filippakopoulos P, Knapp S (2011) Bromodomains as therapeutic targets. Expert Rev Mol Med 13:e29
Padmanabhan B, Mathur S, Manjula R, Tripathi S (2016) Bromodomain and extra-terminal (BET) family proteins: new therapeutic targets in major diseases. J Biosci 41:295–311
Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, Wang J, Chen X, Dong H, Siu K, Winkler JD, Crew AP, Crews CM, Coleman KG (2016) PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci USA 113:7124–7129
Sarthy A, Li L, Albert DH, Lin X, Scott W, Faivre E, Bui MH, Huang X, Wilcox DM, Magoc T, Buchanan FG, Tapang P, Sheppard GS, Wang L, Fidanze SD, Pratt J, Liu D, Hasvold L, Hessler P, Uziel T, Lam L, Rajaraman G, Fang G, Elmore SW, Rosenberg SH, McDaniel K, Kati W, Shen Y (2016) Abstract 4728: ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications. Cancer Res 76:4718
Shapiro GI, Dowlati A, LoRusso PM, Eder JP, Anderson A, Do KT, Kagey MH, Sirard C, Bradner JE, Landau SB (2015) Abstract A49: clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC). Mol Cancer Ther 14:A49
Siu KT, Eda H, Snto L, Ramachandran J, Koulnis M, Mertz J, Sims RJ, Cooper M, Raje NS (2015) Effects of the BET inhibitor, Cpi-0610, alone and in combination with lenalidomide in mumtiple myeloma. Blood 126:4255
Tang X, Peng R, Phillips JE, Deguzman J, Ren Y, Apparsundaram S, Luo Q, Bauer CM, Fuentes ME, DeMartino JA, Tyagi G, Garrido R, Hogaboam CM, Denton CP, Holmes AM, Kitson C, Stevenson CS, Budd DC (2013) Assessment of Brd4 Inhibition in Idiopathic Pulmonary Fibrosis Lung Fibroblasts and in vivo Models of Lung Fibrosis. Am J Pathol 183:470–479
You JS, Han JH (2014) Targeting components of epigenome by small molecules. Arch Pharm Res 37:1367–1374
Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J, Chuang PY, Ohlmeyer M, He JC, Zhou MM (2012) Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem 287:28840–28851
Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR (2011) RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478:524–528
Acknowledgements
The authors are grateful to the Korea Chemical Bank for the supply of compound libraries from Korea Research Institute of Chemical Technology (KRICT). This work was supported by the KRICT (KK1703-G00, SI1707-02, SKO1706H01) and National Research Council of Science and Technology (SKO1707C05).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no conflict of interest to declare.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Yoo, M., Yoo, M., Kim, J.E. et al. Synthesis and biological evaluation of indazole-4,7-dione derivatives as novel BRD4 inhibitors. Arch. Pharm. Res. 41, 46–56 (2018). https://doi.org/10.1007/s12272-017-0978-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-017-0978-y