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CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia

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Summary

Acute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL) and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in the MLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and samples derived from 97 patients. CDKI-73 induced cancer cells undergoing apoptosis through transcriptional downregulation of anti-apoptotic proteins Bcl-2, Mcl-1 and XIAP by majorly targeting CDK9. Contrastively, it was relatively low toxic to the bone marrow cells of healthy donors. In MV4–11 xenograft mouse models, oral administration of CDKI-73 resulted in a marked inhibition of tumor growth (p < 0.0001) and prolongation of animal life span (P < 0.001) without causing body weight loss and other overt toxicities. The study suggests that CDKI-73 can be developed as a highly efficacious and orally deliverable therapeutic agent for treatment of AML.

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References

  1. Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR (2013) Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over three decades. Cancer 119(15):2720–2727. https://doi.org/10.1002/cncr.28129

    Article  PubMed  Google Scholar 

  2. Derolf ÅR, Kristinsson SY, Andersson TM-L, Landgren O, Dickman PW, Björkholm M (2009) Improved patient survival for acute myeloid leukemia: a population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood 113(16):3666–3672. https://doi.org/10.1182/blood-2008-09-179341

    Article  CAS  PubMed  Google Scholar 

  3. Krivtsov AV, Figueroa ME, Sinha AU, Stubbs MC, Feng Z, Valk PJ, Delwel R, Dohner K, Bullinger L, Kung AL, Melnick AM, Armstrong SA (2013) Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia 27(4):852–860. https://doi.org/10.1038/leu.2012.363

    Article  CAS  PubMed  Google Scholar 

  4. Liu W, Deng L, Song Y, Redell M (2014) DOT1L inhibition sensitizes MLL-rearranged AML to chemotherapy. PLoS ONE 9(5):e98270. https://doi.org/10.1371/journal.pone.0098270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Godfrey L, Kerry J, Thorne R, Repapi E, Davies JOJ, Tapia M, Ballabio E, Hughes JR, Geng H, Konopleva M, Milne TA (2017) MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. Exp Hematol 47:64–75. https://doi.org/10.1016/j.exphem.2016.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Horton SJ, Jaques J, Woolthuis C, van Dijk J, Mesuraca M, Huls G, Morrone G, Vellenga E, Schuringa JJ (2013) MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny. Leukemia 27(5):1116–1126. https://doi.org/10.1038/leu.2012.343

    Article  CAS  PubMed  Google Scholar 

  7. Liedtke M, Cleary ML (2009) Therapeutic targeting of MLL. Blood 113(24):6061–6068. https://doi.org/10.1182/blood-2008-12-197061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mueller D, Bach C, Zeisig D, Garcia-Cuellar MP, Monroe S, Sreekumar A, Zhou R, Nesvizhskii A, Chinnaiyan A, Hess JL, Slany RK (2007) A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110(13):4445–4454. https://doi.org/10.1182/blood-2007-05-090514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Martino V, Tonelli R, Montemurro L, Franzoni M, Marino F, Fazzina R, Pession A (2006) Down-regulation of MLL-AF9, MLL and MYC expression is not obligatory for monocyte-macrophage maturation in AML-M5 cell lines carrying t(9;11)(p22;q23). Oncol Rep 15(1):207–211. https://doi.org/10.3892/or.15.1.207

    Article  CAS  PubMed  Google Scholar 

  10. Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary ML (2010) A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell 17(2):198–212. https://doi.org/10.1016/j.ccr.2009.12.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baker A, Gregory GP, Verbrugge I, Kats L, Hilton JJ, Vidacs E, Lee EM, Lock RB, Zuber J, Shortt J, Johnstone RW (2016) The CDK9 inhibitor Dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia. Cancer Res 76(5):1158–1169. https://doi.org/10.1158/0008-5472.CAN-15-1070

    Article  CAS  PubMed  Google Scholar 

  12. Garcia-Cuellar MP, Fuller E, Mathner E, Breitinger C, Hetzner K, Zeitlmann L, Borkhardt A, Slany RK (2014) Efficacy of cyclin-dependent-kinase 9 inhibitors in a murine model of mixed-lineage leukemia. Leukemia 28(7):1427–1435. https://doi.org/10.1038/leu.2014.40

    Article  CAS  PubMed  Google Scholar 

  13. Johnson AJ, Yeh Y-Y, Smith LL, Wagner AJ, Hessler J, Gupta S, Flynn J, Jones J, Zhang X, Bannerji R, Grever MR, Byrd JC (2012) The novel cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells. Leukemia 26(12):2554–2557. https://doi.org/10.1038/leu.2012.144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, Fruth B, Roy V, Erlichman C, Stewart AK (2015) Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood 125(3):443–448. https://doi.org/10.1182/blood-2014-05-573741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu X, Shi S, Lam F, Pepper C, Fischer PM, Wang S (2012) CDKI-71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer cells compared to flavopiridol. Int J Cancer 130(5):1216–1226. https://doi.org/10.1002/ijc.26127

    Article  CAS  PubMed  Google Scholar 

  16. Shao H, Shi S, Huang S, Hole AJ, Abbas AY, Baumli S, Liu X, Lam F, Foley DW, Fischer PM, Noble M, Endicott JA, Pepper C, Wang S (2013) Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities. J Med Chem 56:640–659. https://doi.org/10.1021/jm301475f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Walsby E, Pratt G, Shao H, Abbas AY, Fischer PM, Bradshaw TD, Brennan P, Fegan C, Wang S, Pepper C (2014) A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget 5(2):375–385. https://doi.org/10.18632/oncotarget.1568

    Article  PubMed  Google Scholar 

  18. Lam F, Abbas AY, Shao H, Teo T, Adams J, Li P, Bradshaw TD, Fischer PM, Walsby E, Pepper C, Chen Y, Ding J, Wang S (2014) Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget 5(17):7691–7704. https://doi.org/10.18632/oncotarget.2296

    Article  PubMed  PubMed Central  Google Scholar 

  19. Placke T, Faber K, Nonami A, Putwain SL, Salih HR, Heidel FH, Kramer A, Root DE, Barbie DA, Krivtsov AV, Armstrong SA, Hahn WC, Huntly BJ, Sykes SM, Milsom MD, Scholl C, Frohling S (2014) Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 124(1):13–23. https://doi.org/10.1182/blood-2014-02-558114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Diab S, Teo T, Kumarasiri M, Li P, Yu M, Lam F, Basnet SK, Sykes MJ, Albrecht H, Milne R, Wang S (2014) Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: synthesis, SAR analysis and biological evaluation. ChemMedChem 9(5):962–972. https://doi.org/10.1002/cmdc.201300552

    Article  CAS  PubMed  Google Scholar 

  21. Wu Y, Yao X, Zhu M, Qian H, Jiang L, Lan T, Wu M, Pang J, Chen Y (2016) PKG II reverses HGF-triggered cellular activities by phosphorylating serine 985 of c-Met in gastric cancer cells. Oncotarget 7(23):34190–34200. https://doi.org/10.18632/oncotarget.9074

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tadesse S, Yu M, Mekonnen LB, Lam F, Islam S, Tomusange K, Rahaman MH, Noll B, Basnet SK, Teo T, Albrecht H, Milne R, Wang S (2017) Highly potent, selective, and orally bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine cyclin-dependent kinases 4 and 6 inhibitors as anticancer drug candidates: design, synthesis, and evaluation. J Med Chem 60(5):1892–1915. https://doi.org/10.1021/acs.jmedchem.6b01670

    Article  CAS  PubMed  Google Scholar 

  23. Bansal H, Bansal S, Rao M, Foley KP, Sang J, Proia DA, Blackman RK, Ying W, Barsoum J, Baer MR, Kelly K, Swords R, Tomlinson GE, Battiwalla M, Giles FJ, Lee KP, Padmanabhan S (2010) Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. Blood 116(22):4591–4599. https://doi.org/10.1182/blood-2009-10-247239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Natoni A, Murillo LS, Kliszczak AE, Catherwood MA, Montagnoli A, Samali A, O'Dwyer M, Santocanale C (2011) Mechanisms of action of a dual Cdc7/Cdk9 kinase inhibitor against quiescent and proliferating CLL cells. Mol Cancer Ther 10(9):1624–1634. https://doi.org/10.1158/1535-7163.mct-10-1119

    Article  CAS  PubMed  Google Scholar 

  25. Garriga J, Xie H, Obradovic Z, Grana X (2010) Selective control of gene expression by CDK9 in human cells. J Cell Physiol 222(1):200–208. https://doi.org/10.1002/jcp.21938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Garriga J, Graña X (2014) CDK9 inhibition strategy defines distinct sets of target genes. BMC Res Notes 7:301–301. https://doi.org/10.1186/1756-0500-7-301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang S, Fischer PM (2008) Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology. Trends Pharmacol Sci 29(6):302–313. https://doi.org/10.1016/j.tips.2008.03.003

    Article  CAS  PubMed  Google Scholar 

  28. Morales F, Giordano A (2016) Overview of CDK9 as a target in cancer research. Cell Cycle 15(4):519–527. https://doi.org/10.1080/15384101.2016.1138186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rahaman MH, Kumarasiri M, Mekonnen LB, Yu M, Diab S, Albrecht H, Milne RW, Wang S (2016) Targeting CDK9: a promising therapeutic opportunity in prostate cancer. Endocr Relat Cancer 23(12):T211–T226. https://doi.org/10.1530/erc-16-0299

    Article  CAS  PubMed  Google Scholar 

  30. Choudhary GS, Al-harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, Hsi ED, Almasan A (2015) MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis 6:e1593. https://doi.org/10.1038/cddis.2014.525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pan R, Ruvolo VR, Wei J, Konopleva M, Reed JC, Pellecchia M, Andreeff M, Ruvolo PP (2015) Inhibition of Mcl-1 with the pan–Bcl-2 family inhibitor (−)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood 126(3):363–372. https://doi.org/10.1182/blood-2014-10-604975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bose P, Grant S (2013) Mcl-1 as a therapeutic target in acute myelogenous leukemia (AML). Leuk Res Rep 2(1):12–14. https://doi.org/10.1016/j.lrr.2012.11.006

    Article  PubMed  PubMed Central  Google Scholar 

  33. Glaser SP, Lee EF, Trounson E, Bouillet P, Wei A, Fairlie WD, Izon DJ, Zuber J, Rappaport AR, Herold MJ, Alexander WS, Lowe SW, Robb L, Strasser A (2012) Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev 26(2):120–125. https://doi.org/10.1101/gad.182980.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Karami H, Baradaran B, Esfahani A, Sakhinia M, Sakhinia E (2014) Therapeutic effects of myeloid cell Leukemia-1 siRNA on human acute myeloid leukemia cells. Adv Pharm Bull 4(3):243–248. https://doi.org/10.5681/apb.2014.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Thomas D, Powell JA, Vergez F, Segal DH, Nguyen NY, Baker A, Teh TC, Barry EF, Sarry JE, Lee EM, Nero TL, Jabbour AM, Pomilio G, Green BD, Manenti S, Glaser SP, Parker MW, Lopez AF, Ekert PG, Lock RB, Huang DC, Nilsson SK, Recher C, Wei AH, Guthridge MA (2013) Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood 122(5):738–748. https://doi.org/10.1182/blood-2012-08-447441

    Article  CAS  PubMed  Google Scholar 

  36. Carter BZ, Milella M, Tsao T, McQueen T, Schober WD, Hu W, Dean NM, Steelman L, McCubrey JA, Andreeff M (2003) Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia. Leukemia 17(11):2081–2089. https://doi.org/10.1038/sj.leu.2403113

    Article  CAS  PubMed  Google Scholar 

  37. Shapiro GI (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24(11):1770–1783. https://doi.org/10.1200/JCO.2005.03.7689

    Article  CAS  PubMed  Google Scholar 

  38. Booher RN, Hatch H, Dolinski BM, Nguyen T, Harmonay L, Al-Assaad AS, Ayers M, Nebozhyn M, Loboda A, Hirsch HA, Zhang T, Shi B, Merkel CE, Angagaw MH, Wang Y, Long BJ, Lennon XQ, Miselis N, Pucci V, Monahan JW, Lee J, Kondic AG, Im EK, Mauro D, Blanchard R, Gilliland G, Fawell SE, Zawel L, Schuller AG, Strack P (2014) MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis. PLoS ONE 9(10):e108371. https://doi.org/10.1371/journal.pone.0108371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. De Biasio A, Vrana JA, Zhou P, Qian L, Bieszczad CK, Braley KE, Domina AM, Weintraub SJ, Neveu JM, Lane WS, Craig RW (2007) N-terminal truncation of Antiapoptotic MCL1, but not G2/M-induced phosphorylation, is associated with stabilization and abundant expression in tumor cells. J Biol Chem 282(33):23919–23936. https://doi.org/10.1074/jbc.M700938200

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Muhammed H. Rahaman and Longjin Zhong acknowledge the support from the Australian Government Research Training Program Scholarship. We especially acknowledge the contribution of patients.

Funding

This work was partially supported by Channel 7 Children’s Research Foundation (Grant number 161300) and the Tour de Cure’s established Grant to SW.

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Author notes

  1. Muhammed H. Rahaman, Yingyi Yu and Longjin Zhong contributed equally to this work.

Authors and Affiliations

  1. Centre for Drug Discovery and Development, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, Australia

    Muhammed H. Rahaman, Longjin Zhong, Julian Adams, Frankie Lam, Peng Li, Ben Noll, Robert Milne & Shudong Wang

  2. Department of Haematology, Qilu Hospital, Shandong University, Jinan, People’s Republic of China

    Yingyi Yu & Jun Peng

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  1. Muhammed H. Rahaman
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Correspondence to Jun Peng or Shudong Wang.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Rahaman, M.H., Yu, Y., Zhong, L. et al. CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia. Invest New Drugs 37, 625–635 (2019). https://doi.org/10.1007/s10637-018-0661-2

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