title: 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-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.
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Cliff C
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: José S
authors.initials: JS
authors.lastname: Duca
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Xianshu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Richards
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
keywords: Automated Ligand Identification System (ALIS); CHK1 protein kinase; affinity selection−mass spectrometry (AS-MS); structure-based drug design; thiazole-4-carboxamide