Keeping checkpoint kinases in line: new selective inhibitors in clinical trials

Background: Checkpoint kinase 1 (Chk1), a serine/threonine kinase, functions as a regulatory kinase in cell cycle progression and is a critical effector of the DNA-damage response. Inhibitors of Chk1 are known to sensitise tumours to a variety of DNA-damaging agents and increase efficacy in preclinical models. Objective: The most advanced agents are now in Phase I clinical trials; the preclinical profiles of these drugs are compared and contrasted, together with a discussion of some of the opportunities and challenges facing this potentially revolutionary approach to cancer therapy. Methods: A review of the publications and presentations on XL-844, AZD7762 and PF-477736. Results/conclusions: Chk kinases are part of the DNA damage recognition and response pathways and as such represent attractive targets. Agents that target checkpoint kinases have demonstrated impressive evidence preclinically that this approach will provide tumour-specific potentiating agents and may have broad therapeutic utility.