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.

Mike I Walton,Gary Box,Paul D Eve,Alan T Henley,Florence I Raynaud,Michelle D Garrett,Neil D Perkins,Michael Lainchbury,Angela Hayes,Ian Collins,Thomas P Matthews,G Wynne Aherne,Matthew Tall,Suzanne A Eccles,Alexis K De Haven Brandon,Jill E Hunter,T Mchardy ,James D Osborne ,Kathy Boxall ,Karen E Swales ,Melanie Valenti ,John Reader

doi:10.18632/oncotarget.4919

Abstract

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.

Highlights

The DNA damage response (DDR) pathway has evolved to protect cells from genetic insults in an effort to preserve genomic integrity and cell viability [1, 2]
A model of CCT245737 bound in the ATP pocket of human CHK1 is shown in Supplementary Figure S1 and suggests that key interactions in the ATP binding site have been retained through hydrogen bonding to Glu85 and Cys87 in the hinge region, the hydrogen bonding of the nitrile to Lys38, while the basic nitrogen on the morpholine forms a salt bridge to Glu91
Enzyme kinetic and modeling data clearly show that CCT245737 is a potent, ATPcompetitive inhibitor of human CHK1 kinase with an IC50 of 1.4nM

Summary

Introduction

The DNA damage response (DDR) pathway has evolved to protect cells from genetic insults in an effort to preserve genomic integrity and cell viability [1, 2]. A hallmark of many tumors is the lack of functional p53 protein with a consequent loss of the G1/S checkpoint leading to a potential increase in reliance on the S and G2/M checkpoints for survival following genotoxic stress [5]. This has stimulated the development of selective www.impactjournals.com/oncotarget. G2 checkpoint inhibitors for combination with DNA damaging anticancer drugs [6,7,8,9]. As a result of promising early studies, several CHK1 inhibitors have been developed and are currently undergoing clinical evaluation in combination with genotoxic drugs [6, 8, 14,15,16]

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Results

Conclusion