A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine
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Elisabeth Walsby1, Guy Pratt2, Hao Shao3, Abdullah Y. Abbas3, Peter M. Fischer3, Tracey D. Bradshaw3, Paul Brennan1, Chris Fegan1, Shudong Wang3,4 and Chris Pepper1
1 Cardiff CLL Research Group, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
2 CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, UK.
3 School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
4 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
Chris Pepper, email:
Keywords: CLL, cdk9, synergy, MCL1
Received: November 3, 2013 Accepted: December 18, 2013 Published: December 18, 2013
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.
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