A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine.
Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 was more potent than the pan-cdk inhibitor flavopiridol and showed >200-fold selectivity against primary leukemia cells when compared with normal CD34+ cells. Furthermore, CDKI-73 was equipotent in poor prognostic sub-groups of leukemia patients and showed cytotoxic synergy with the nucleoside analog fludarabine. The Mechanism of synergy was associated with CDKI-73-mediated transcriptional inhibition of MCL1 and XIAP that was maintained when used in combination with fludarabine. Our data present a strong rationale for the development of cdk9 inhibitors such as CDKI-73 as anticancer therapeutics.
Cardiff CLL Research Group, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
Elisabeth
E
Walsby
Guy
G
Pratt
Hao
H
Shao
Abdullah Y
AY
Abbas
Peter M
PM
Fischer
Tracey D
TD
Bradshaw
Paul
P
Brennan
Chris
C
Fegan
Shudong
S
Wang
Chris
C
Pepper
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D016022:Case-Control Studies; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000235:genetics; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000096926:Benzenesulfonamides
D042863:Cyclin-Dependent Kinase 9; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D014740:Vidarabine; C000599930:3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzenesulfonamide; D000096926:Benzenesulfonamides; C467969:CDK9 protein, human; C024352:fludarabine