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.