The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma
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Mike I. Walton1, Paul D. Eve1, Angela Hayes1, Alan T. Henley1, Melanie R. Valenti1, Alexis K. De Haven Brandon1, Gary Box1, Kathy J. Boxall1, Matthew Tall1, Karen Swales1, Thomas P. Matthews1, Tatiana McHardy1, Michael Lainchbury1, James Osborne1, Jill E. Hunter2, Neil D. Perkins2, G. Wynne Aherne1, John C. Reader3, Florence I. Raynaud1, Suzanne A. Eccles1, Ian Collins1 and Michelle D. Garrett1,4
1 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
2 Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle Upon Tyne, UK
3 Sareum Ltd, Cambridge, UK
4 School of Biosciences, University of Kent, Canterbury, Kent, UK
Mike I. Walton, email:
Michelle D. Garrett, email:
Keywords: CHK1, CCT245737, pharmacology, antitumor activity, biomarker assay
Received: April 30, 2015 Accepted: July 11, 2015 Published: July 22, 2015
CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.
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