Targeting the DNA Damage Response with a Selective CHK1 Inhibitor


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Ian Collins1
1The Institute of Cancer Research

Abstract

Genome instability is a hallmark trait of cancer, and cancer cells incur increased replication stress and potential for DNA damage as a result. The proteins that mediate cellular responses to DNA damage and replication stress present tumour-specific vulnerabilities for therapeutic intervention.  Checkpoint kinase 1 (CHK1) is a central component of the DNA damage response and repair signalling pathways and CHK1 inhibitors have potential for use as mono-therapy or in combination with other agents. We used structure-based drug design together with mechanistic cellular assays to optimize potent and highly selective small molecule inhibitors of CHK1, leading to the identification of a clinical candidate CHK1 inhibitor.  In parallel, the selective compounds we discovered proved useful as preclinical tools to understand the most effective drug combinations and cancer cell sensitivities to CHK1 inhibition, and to define the contexts for clinical trials.