Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

Abstract

A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-<i>N</i>-(2-(piperazin-1-yl)­phenyl)­thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection–mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2