Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)

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• 作者：Yun Ding ; Heather O鈥橩eefe ; Jennifer L. DeLorey ; David I. Israel ; Jeffrey A. Messer ; Cynthia H. Chiu ; Steven R. Skinner ; Rosalie E. Matico ; Monique F. Murray-Thompson ; Fan Li ; Matthew A. Clark ; John W. Cuozzo ; Christopher Arico-Muendel ; Barry A. Morgan
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：888-893
• 全文大小：377K
• ISSN：1948-5875

文摘

The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure鈥揳ctivity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide has IC₅₀ of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.