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ACS Med Chem Lett. 2015 Jul 7;6(8):888-93. doi: 10.1021/acsmedchemlett.5b00138. eCollection 2015 Aug 13.

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

Author information

1
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
2
Tedor Pharma, Inc. , 400 Highland Corporate Drive, Cumberland, Rhode Island 02864, United States.
3
Biological Reagent and Assay Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
4
Tufts Healthcare Institute , 136 Harrison Avenue, Boston, Massachusetts 02111, United States.
5
X-Chem, Inc. , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
6
Center for Drug Discovery, Baylor College of Medicine , One Baylor Plaza, Houston, Texas 77030, United States.

Abstract

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-activity 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.

KEYWORDS:

ADAMTS-4; DNA-encoded library; inhibitors

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