Skip to main content

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

Walton, Mike I., Eve, Paul D., Hayes, Angela, Henley, Alan T., Valenti, Melanie R., De Haven Brandon, Alexis K., Boxall, Kathy J., Box, Gary, Tall, Matthew, Swales, Karen, and others. (2015) 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. Oncotarget, 7 (3). pp. 2329-2342. E-ISSN 1949-2553. (doi:10.18632/oncotarget.4919) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:54924)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://doi.org/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.

Item Type: Article
DOI/Identification number: 10.18632/oncotarget.4919
Uncontrolled keywords: CHK1, CCT245737, pharmacology, antitumor activity, biomarker assay
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 13 Apr 2016 09:05 UTC
Last Modified: 13 Mar 2020 04:07 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/54924 (The current URI for this page, for reference purposes)
Garrett, Michelle D.: https://orcid.org/0000-0002-3939-1673
  • Depositors only (login required):