The Discovery of Checkpoint Kinase 1 Inhibitors: From Fragments to Clinical Candidate

Abstract

Selective inhibitors of the DNA damage response Checkpoint Kinase 1 (CHK1) for the treatment of cancer were discovered by a fragment-based approach. Structure-based optimisation with iterative protein crystallography gave well-characterised chemical tool inhibitors, which enabled a better understanding of the biology of CHK1 inhibition and validated new potential clinical contexts. Multi-parameter optimisation identified the candidate drug SRA737, taken forward to clinical development in combinations with chemotherapy and as a single agent. The project involved close partnerships between academic discovery laboratories and biotechnology companies, drawing on national collaborative networks, charitable grants and venture capital funding to progress the joint drug discovery objectives.