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The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS
Mike I Walton1, Paul D Eve1, Angela Hayes1
1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
Abstract:
CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) 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.
Insights
CCT245737, a novel CHK1 inhibitor, shows potent and selective activity, enhancing chemotherapy efficacy and demonstrating therapeutic advantage in preclinical models. This orally active drug is advancing to Phase I clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Checkpoint kinase 1 (CHK1) is a key regulator of DNA damage response.
- Inhibiting CHK1 can sensitize cancer cells to DNA-damaging agents.
- Developing orally active CHK1 inhibitors with high selectivity is a therapeutic goal.
Purpose of the Study:
- To introduce CCT245737, the first orally active CHK1 inhibitor in clinical development.
- To evaluate the preclinical efficacy and pharmacokinetic profile of CCT245737.
- To assess the combination therapy of CCT245737 with chemotherapy in various cancer models.
Main Methods:
- Biochemical assays to determine enzyme inhibition (IC50) and selectivity.
- In vitro studies using human tumor cell lines to assess cytotoxicity.
- In vivo studies using human tumor xenograft and mouse models to evaluate efficacy, pharmacokinetics, and target engagement.
- Development of a novel ELISA assay for pS296 CHK1 autophosphorylation.
Main Results:
- CCT245737 demonstrated potent CHK1 inhibition (IC50 1.4 nM) with >1,000-fold selectivity over CHK2 and CDK1.
- The drug exhibited complete oral bioavailability (100%) in mice with extensive tumor exposure.
- CCT245737 significantly enhanced gemcitabine and SN38 cytotoxicity, showing a greater antitumor effect than single agents without increased toxicity.
- Target inhibition was successfully measured in vivo using the novel pS296 CHK1 ELISA assay.
- CCT245737 showed single-agent activity in a MYC-driven B-cell lymphoma model.
Conclusions:
- CCT245737 is a promising clinical development candidate for CHK1 inhibition.
- The combination of CCT245737 with gemcitabine offers a true therapeutic advantage in preclinical cancer models.
- The novel pS296 CHK1 ELISA assay is a valuable tool for monitoring target inhibition in clinical trials.
- CCT245737 is scheduled for a first-in-human Phase I clinical trial.
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