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

Xiaohua Huang; Cliff C Cheng; Thierry O Fischmann; José S Duca; Xianshu Yang; Matthew Richards; Gerald W Shipps Jr

doi:10.1021/ml200249h

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

ACS Med Chem Lett. 2012 Jan 20;3(2):123-8. doi: 10.1021/ml200249h. eCollection 2012 Feb 9.

Authors

Xiaohua Huang¹, Cliff C Cheng¹, Thierry O Fischmann¹, José S Duca¹, Xianshu Yang¹, Matthew Richards¹, Gerald W Shipps Jr¹

Affiliation

¹ Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.

Abstract

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.

Keywords: Automated Ligand Identification System (ALIS); CHK1 protein kinase; affinity selection−mass spectrometry (AS-MS); structure-based drug design; thiazole-4-carboxamide.