Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode
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- 作者：Xiaohua Huang ; Cliff C. Cheng ; Thierry O. Fischmann ; Jos茅 S. Duca ; Xianshu Yang ; Matthew Richards ; Gerald W. Shipps ; Jr.
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：February 9, 2012
- 年：2012
- 卷：3
- 期：2
- 页码：123-128
- 全文大小：412K
- 年卷期：v.3,no.2(February 9, 2012)
- ISSN：1948-5875
文摘
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鈥搈ass 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.