Oncotarget

Research Papers:

A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine

Elisabeth Walsby, Guy Pratt, Hao Shao, Abdullah Y. Abbas, Peter M. Fischer, Tracey D. Bradshaw, Paul Brennan, Chris Fegan, Shudong Wang and Chris Pepper _

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Oncotarget. 2014; 5:375-385. https://doi.org/10.18632/oncotarget.1568

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Abstract

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.

Correspondence:

Chris Pepper, email:

Keywords: CLL, cdk9, synergy, MCL1

Received: November 3, 2013 Accepted: December 18, 2013 Published: December 18, 2013

Abstract

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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