A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models

Molecular Cancer Therapeutics

Volumn 13, Issue 6, 2014, Pages 1442-1456

  Yin, Tinggui ^a   Lallena, Maria J ^b   Kreklau, Emiko L ^a   Fales, Kevin R ^a   Carballares, Santiago ^b   Torrres, Raquel ^b   Wishart, Graham N ^a   Ajamie, Rose T ^a   Cronier, Damien M ^a   Iversen, Phillip W ^a   Meier, Timothy I ^a   Foreman, Robert T ^a   Zeckner, Douglas ^a   Sissons, Sean E ^a   Halstead, Bart W ^a   Lin, Aimee B ^a   Donoho, Gregory P ^a   Qian, Yuewei ^a   Li, Shuyu ^a   Wu, Song ^a   Aggarwal, Amit ^a   Ye, Xiang S ^a   Starling, James J ^a   Gaynor, Richard B ^a   De Dios, Alfonso ^a   Du, Jian ^a   more..

^a ELI LILLY AND COMPANY   (United States)

^b ELI LILLY AND COMPANY   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CYCLIN DEPENDENT KINASE 9; ENZYME INHIBITOR; FLAVOPIRIDOL; LY 2857785; PROTEIN MCL 1; RAPAMYCIN; RNA POLYMERASE II; UNCLASSIFIED DRUG; [N1 [4 (3 ISOPROPYL 2 METHYLINDAZOL 5 YL)PYRIMIDIN 2 YL] N4 TETRAHYDROPYRAN 4 YL CYCLOHEXANE TRANS 1,4 DIAMINE METHANESULFONIC ACID; CDK9 PROTEIN, HUMAN; CYCLOHEXYLAMINE DERIVATIVE; INDAZOLE DERIVATIVE; MCL1 PROTEIN, HUMAN; MYELOID LEUKEMIA FACTOR 1; N1-(4-(3-ISOPROPYL-2-METHYLINDAZOL-5-YL)PYRIMIDIN-2-YL)-N4-TETRAHYDROPYRAN-4-YL-CYCLOHEXANE-1,4-DIAMINE; SERINE;

ACUTE GRANULOCYTIC LEUKEMIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; BONE MARROW TOXICITY; CANCER CELL LINE; CANCER INHIBITION; CELL KILLING; CELL PROLIFERATION; CHRONIC LYMPHATIC LEUKEMIA; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; DRUG TARGETING; ENZYME INHIBITION; EX VIVO STUDY; FEMALE; GENETIC TRANSCRIPTION; HEMATOLOGIC MALIGNANCY; HUMAN; HUMAN CELL; LEUKEMIA CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RAT; SOLID TUMOR; TUMOR CELL; TUMOR MODEL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; DRUG EFFECTS; GENETICS; LEUKEMIA; METABOLISM; PATHOLOGY; PHOSPHORYLATION; TUMOR CELL LINE;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; CYCLIN-DEPENDENT KINASE 9; CYCLOHEXYLAMINES; HUMANS; INDAZOLES; LEUKEMIA; MYELOID CELL LEUKEMIA SEQUENCE 1 PROTEIN; PHOSPHORYLATION; SERINE;

EID: 84902665582     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-13-0849     Document Type: Article

References (47)

1. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009;9:153-66.
2. Thomas MC, Chiang CM. The general transcription machinery and general cofactors. Crit Rev Biochem Mol Biol 2006;41:105-78.
3. Cicenas J, Valius M. The CDK inhibitors in cancer research and therapy. J Cancer Res Clin Oncol 2011;137:1409-18.
4. Romano G, Giordano A. Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and human diseases. Cell Cycle 2008;7:3364-8.
5. Krystof V, Uldrijan S. Cyclin-dependent kinase inhibitors as anti-cancer drugs. Curr Drug Targets 2010;11:291-302.
6. Ramanathan Y, Rajpara SM, Reza SM, Lees E, Shuman S, Mathews MB, et al. Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences. J Biol Chem 2001;276:10913-20. (Pubitemid 38089269)
7. Guo Z, Stiller JW. Comparative genomics of cyclin-dependent kinases suggest co-evolution of the RNAP II C-terminal domain and CTD-directed CDKs. BMC Genomics 2004;5:69.
8. Pinhero R, Liaw P, Bertens K, Yankulov K. Three cyclin-dependent kinases preferentially phosphorylate different parts of the C-terminal domain of the large subunit of RNA polymerase II. Eur J Biochem 2004;271:1004-14. (Pubitemid 38299654)
9. Dubois MF, Vincent M, Vigneron M, Adamczewski J, Egly JM, Bensaude O. Heat-shock inactivation of the TFIIH-associated kinase and change in the phosphorylation sites on the C-terminal domain of RNA polymerase II. Nucleic Acid Res 1997;25:694-700. (Pubitemid 27299821)
10. Trigon S, Serizawa H, Conaway JW, Conaway RC, Jackson SP, Morange M. Characterization of the residues phosphorylated in vitro by different C-terminal domain kinases. J Biol Chem 1998;273:6769-75. (Pubitemid 28160339)
11. Rickert P, Corden JL, Lees E. Cyclin C/CDK8 and cyclin H/CDK7/ p36 are biochemically distinct CTD kinases. Oncogene 1999;18:1093-102. (Pubitemid 29086287)
12. Chapman RD, Heidemann M, Albert TK, Mailhammer M, Flatley A, Meisterernst M, et al. Transcribing RNA polymerase II is phosphorylated at CTD residue serine-7. Science 2007;318:1780-2. (Pubitemid 350274389)
13. Fisher RP, Morgan DO. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell 1994;78:713-24. (Pubitemid 24268593)
14. Wallenfang MR, Seydoux G. Cdk-7 is required for mRNA transcription and cell cycle progression in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 2002;99:5527-32. (Pubitemid 34411582)
15. Schwartz BE, Larochelle S, Suter B, Lis JT. Cdk7 is required for full activation of Drosophila heat shock genes and RNA polymerase II phosphorylation in vivo . Mol Cell Biol 2003;23:6876-86. (Pubitemid 37214657)
16. Lee KM, Miklos I, Du H, Watt S, Szilagyi Z, Saiz JE, et al. Impairment of the TFIIH-associated CDK-activating kinase selectively affects cell cycle-regulated gene expression in fission yeast. Mol Biol Cell 2005;16:2734-45. (Pubitemid 40741220)
17. Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, et al. CDK8 is a colorectal cancer oncogene that regulates b-catenin activity. Nature 2008;455:547-51.
18. Mancebo HSM, Lee G, Flygare J, Tomassini J, Luu P, Zhu Y, et al. PTEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro. Genes Dev 1997;11:2633-44. (Pubitemid 27452387)
19. Gomes NP, Bjerke G, Llorente B, Szostek SA, Emerson BM, Espinosa JM. Gene-specific requirement for P-TEFb activity and RNA polymerase II phosphorylation within the p53 transcriptional program. Genes Dev 2006;20:601-12. (Pubitemid 43345325)
20. Li Q, Price JP, Byers SA, Cheng D, Peng J, Price DH. Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. J Biol Chem 2005;280:28819-26. (Pubitemid 41105784)
21. Eissenberg JC, Shilatifard A, Dorokhov N, Michener DE. Cdk9 is an essential kinase in Drosophila that is required for heat shock gene expression, histone methylation and elongation factor recruitment. Mol Gen Genomics 2006;277:101-14. (Pubitemid 46208345)
22. McInnes C. Progress in the evaluation of CDK inhibitors as anti-tumor agents. Drug Disc Today 2008;13:875-81.
23. Yoo KY, Kang D. Current researches on breast cancer epidemiology in Korea. Breast Cancer 2003;10:289-93.
24. Bellan C, De Falco G, Lazzi S, Micheli P, Vicidomini S, Schurfeld K, et al. CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation. J Pathol 2004;203:946 -52.
25. Shan B, Zhuo Y, Chin D, Morris CA, Morris GF, Lasky JA. Cyclindependent kinase 9 is required for tumor necrosis factor-a-stimulated matrix metalloproteinase-9 expression in human lung adenocarcinoma cells. J Biol Chem 2005;280:1103-11.
26. De Falco G, Bellan C, D'Amuri A, Angeloni G, Leucci E, Giordano A, et al. Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors. Cancer Biol Ther 2005;4:277-81. (Pubitemid 41351286)
27. Cai D, Latham VM, Zhang X, Shapiro GI. Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res 2006;66:9270-80. (Pubitemid 44521149)
28. Li Y, Jin G, Wang H, Liu H, Qian J, Gu S, et al. Polymorphisms of CAK genes and risk for lung cancer: a case - control study in Chinese population. Lung Cancer 2007;58:171-83. (Pubitemid 47513254)
29. Cunningham JM, Vierkant RA, Sellers TA, Phelan C, Rider DN, Liebow M, et al. Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis. Br J Cancer 2009;101:1461-8.
30. Jeon S, Choi JY, Lee KM, Park SK, Yoo KY, Noh DY, et al. Combined genetic effect of CDK7 and ESR1 polymorphisms on breast cancer. Breast Cancer Res Treat 2010;121:737-42
31. Chen R, Keating MJ, Gandhi V, Plunkett M. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood 2005;106:2513-9. (Pubitemid 41510827)
32. Byrd JC, Peterson BL, Gabrilove J, Odenike OM, Grever MR, Rai K, et al. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from cancer and leukemia group B study 19805. Cancer Ther Clin 2005;11:4176-81. (Pubitemid 40791583)
33. Phelps MA, Lin TS, Johnson AJ, Hurh E, Rozewski DM, Farley KL, et al. Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood 2009;113:2637-45.
34. Blum W, Phelps MA, Klisovic RB, Rozewski DM, Ni W, Albanese KA, et al. Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias. Haematologica 2010;95:1098-105.
35. Karp JE, Blackforda A, Smitha BD, Alinoa K, Seunga AH, Bolaños-Meadea J, et al. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poorrisk acute myelogenous leukemia. Leukemia Res 2010;34:877-82.
36. Lin TS, Blum KA, Fischer DB, Mitchell SM, Ruppert AS, Porcu P, et al. Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders. J Clin Oncol 2010;28:418-23.
37. Krumbach R, Schüler J, Hofmann M, Giesemann T, Fiebig HH, Beckers T. Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. Eur J Cancer 2011;47:1231-43.
38. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448:439-44. (Pubitemid 47123510)
39. Fiebig HH, Schüler J, Bausch N, Hofmann M, Metz T, Korrat A. Gene signatures developed from patient tumor explants grown in nude mice to predict tumor response to 11 cytotoxic drugs. Cancer Genomics Proteomics 2007;4:197-209.
40. Torres-Guzmán R, Chu S, Velasco JA, Lallena MJ. Multiparametric cell-based assay for the evaluation of transcription inhibition by high-content imaging. J Biomol Screen 2013;18:556-66.
41. Fiebig HH, Vuaroqueaux V, Korrat A, Fuoucault F, Beckers T. Predictive gene signatures for bevacizumab and cetuximab as well as cytotoxic agents. Inter J Clin Pharma Ther 2012;50:70 -1.
42. Van Den Heuvel RL, Leppens H, Schoeters GE. Use of in vitro assays to assess hematotoxic effects on environmental compounds. Cell Biol Toxicol 2001;17:107-16. (Pubitemid 32684564)
43. Matsumura-Takeda K, Kotosai K, Ozaki A, Hara H, Yamashita S. Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity. Toxicol in vitro 2002; 16:281-8. (Pubitemid 34521702)
44. Clarke E, Pereira C, Chaney R, Woodside S, Eaves AC, Damen J. Toxicity testing using hematopoietic stem cell assays. Regen Med 2007;2:947-56.
45. Pessina A, Albella B, Bueren J, Brantom P, Casati S, Gribaldo L, et al. Prevalidation of a model for predicting acute neutropenia by colony forming unit granulocyte/macrophage (CFU-GM) assay. Toxicol In Vitro 2001;15:729-40. (Pubitemid 33043962)
46. Pessina A, Albella B, Bayo M, Bueren J, Brantom P, Casati S, et al. Application of the GM-CFU assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive Xenobiotics. Toxicol Sci 2003;75:355-67. (Pubitemid 37220283)
47. Meltzer EB, Barry WT, D'Amico TA, Davis RD, Lin SS, Onaitis MW, et al. Bayesian probit regression model for the diagnosis of pulmonary fibrosis: proof-of-principle. BMC Med Genomics 2011; 4:1-13.