Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia.
Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in chronic lymphocytic leukemia cells by inhibiting Cdk7 and Cdk9, which control transcription. Here we studied the novel Cdk inhibitor SNS-032, which exhibits potent and selective inhibitory activity against Cdk2, Cdk7, and Cdk9. We hypothesized that transient inhibition of transcription by SNS-032 would decrease antiapoptotic proteins, resulting in cell death. SNS-032 effectively killed chronic lymphocytic leukemia cells in vitro regardless of prognostic indicators and treatment history. This was associated with inhibition of phosphorylation of RNA polymerase II and inhibition of RNA synthesis. Consistent with the intrinsic turnover rates of their transcripts and proteins, antiapoptotic proteins, such as Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), were rapidly reduced on exposure to SNS-032, whereas Bcl-2 protein was not affected. The initial decrease of Mcl-1 protein was the result of transcriptional inhibition rather than cleavage by caspase. Compared with flavopiridol and roscovitine, SNS-032 was more potent, both in inhibition of RNA synthesis and at induction of apoptosis. SNS-032 activity was readily reversible; removal of SNS-032 reactivated RNA polymerase II, which led to resynthesis of Mcl-1 and cell survival. Thus, these data support the clinical development of SNS-032 in diseases that require short-lived oncoproteins for survival.
Chen
Rong
R
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Wierda
William G
WG
Chubb
Sherri
S
Hawtin
Rachael E
RE
Fox
Judith A
JA
Keating
Michael J
MJ
Gandhi
Varsha
V
Plunkett
William
W
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010080:Oxazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077546:Roscovitine; D013844:Thiazoles / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
D005419:Flavonoids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D012334:RNA, Neoplasm; D013844:Thiazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077546:Roscovitine; C077990:alvocidib; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D020169:Caspases