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

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journal contribution
posted on 2012-02-09, 00:00 authored by Xiaohua Huang, Cliff C. Cheng, Thierry O. Fischmann, José S. Duca, Xianshu Yang, Matthew Richards, Gerald W. Shipps
A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(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.