AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples

Molecular Cancer Therapeutics

Volumn 9, Issue 4, 2010, Pages 920-928

  Squires, Matthew S ^a   Cooke, Laurence ^b   Lock, Victoria ^a   Qi, Wenqing ^b   Lewis, E Jonathan ^a   Thompson, Neil T ^a   Lyons, John F ^a   Mahadevan, Daruka ^b  

^a ASTEX PHARMACEUTICALS   (United Kingdom)

^b UNIVERSITY OF ARIZONA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AT7519; CYCLIN DEPENDENT KINASE INHIBITOR; N (4 PIPERIDINYL) 4 (2,6 DICHLOROBENZOYLAMINO) 1H PYRAZOLE 3 CARBOXAMIDE; PROTEIN BCL 2; PROTEIN MCL 1; RNA POLYMERASE II; UNCLASSIFIED DRUG; X LINKED INHIBITOR OF APOPTOSIS;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CELL CYCLE REGULATION; CHRONIC LYMPHATIC LEUKEMIA; CONTROLLED STUDY; CYTOTOXICITY; DOWN REGULATION; DRUG EFFECT; DRUG TOLERABILITY; HUMAN; HUMAN CELL; IC 50; LEUKEMIA CELL LINE; MALE; MONONUCLEAR CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROGNOSIS; PROTEIN PHOSPHORYLATION; SINGLE DRUG DOSE; TRANSCRIPTION INITIATION; TUMOR VOLUME;

APOPTOSIS REGULATORY PROTEINS; CELL DEATH; CELL LINE, TUMOR; CYCLIN-DEPENDENT KINASES; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; LEUKEMIA; PIPERIDINES; PYRAZOLES; RNA POLYMERASE II; TIME FACTORS; TRANSCRIPTION, GENETIC; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 77950825064     PISSN: 15357163     EISSN: None     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-09-1071     Document Type: Article

References (19)

1. Wyatt PG, Woodhead AJ, Berdini V, et al. Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment based X-ray crystallography and structure based drug design. J Med Chem 2008;51:4986-4999
2. Squires MS, Feltell RE, Wallis NG, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther 2009;8:324-332
3. Mahadevan D, Plummer R, Squires MS, et al. A dose escalation, pharmacokinetic and pharmacodynamic study of AT7519, a cyclin dependent kinase inhibitor in patients with advanced solid malignancies. ASCO Annual Meeting, Poster Presentation; 2008 May 30-Jun 3; Chicago, Illinois. Abstract 3533.
4. Garriga J, Grana X. Cellular control of gene expression by T-type cyclln/CDK9 complexes. Gene 2004;337:15-23. (Pubitemid 38970101)
5. Lam LT, Pickeral OK, Peng AC, et al. Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol 2001;2:1-11.
6. Pinhero R, Liaw P, Bertens K, Yankulov K. Three cyclin dependent kinases preferentially phosphorylate different parts of the C-terminal domain of the large subunlt of RNA polymerase II. Eur J Biochem 2004;271:1004-1014 (Pubitemid 38299654)
7. Byrd JC, Stilgenbauer S, Flinn IW. Chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2004:163-183
8. O'Brien S. New Agents in the treatment of CLL. Hematology Am Soc Hematol Educ Program 2008:457-464
9. Sherr CJ. Cancer cell cycles. Science 1996;274:1672-1677
10. Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin-dependent kinases (CDKs), growth su ppressor genes and cyclin-dependent kinase Inhibitors (CKIs). Oncogene 1995;11:211-219
11. Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007;109:399-404.
12. Phelps MA, Lin TS, Johnson AJ, 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; 113:2637-2645
13. Hahntow IN, Schneller F, Oelsner M, et al. Cyclin-dependent kinase Inhibitor roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 2004;18:747-755 (Pubitemid 38500193)
14. Chen R, Wierda WG, Chubb S, et al. Mechanism of action of SNS032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood 2009; 113:4637-4645
15. Del Principe MI, Del Poeta G, Buccisano F, et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 2007;108:853-861
16. Zanotti R, Ambrosetti A, Lestani M, et al. ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor. Leukemia 2007; 21:102-109 (Pubitemid 44921841)
17. Chen J, McMillan NA. Molecular basis of pathogenesis, prognosis and therapy in chronic lymphocytic leukemia. Cancer Biol Ther 2008;7:174-179 (Pubitemid 351590419)
18. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975;46: 219-234
19. Petlickovski A, Laurenti L, Li X, et al. Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood 2005;105:4820-4827