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

被引：64

作者：

Ding, Yun ^{[1
]}

O'Keefe, Heather ^{[1
]}

DeLorey, Jennifer L. ^{[2
]}

Israebt, David I. ^{[1
]}

Messer, Jeffrey A. ^{[1
]}

Chiu, Cynthia H. ^{[1
]}

Skinner, Steven R. ^{[1
]}

Matico, Rosalie E. ^{[4
]}

Murray-Thompson, Monique F. ^{[4
]}

Li, Fan ^{[5
]}

Clark, Matthew A.

Cuozzo, John W. ^{[3
]}

Arico-Muendel, Christopher ^{[1
,3
]}

Morgan, Barry A. ^{[6
]}

机构：

[1] ELT Boston, Platform Technol & Sci, GlaxoSmithKline, Waltham, MA 02451 USA

[2] Tedor Pharma Inc, Cumberland, RI 02864 USA

[3] Xchem Inc, Waltham, MA 02453 USA

[4] GlaxoSmithKline, Biol Reagent & Assay Dev, King Of Prussia, PA 19406 USA

[5] Tufts Healthcare Inst, Boston, MA 02111 USA

[6] Ctr Drug Discovery, Baylor Coll Med, Houston, TX 77030 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 08期

关键词：

DNA-encoded library; ADAMTS-4; inhibitors; AGGRECAN DEGRADATION;

D O I：

10.1021/acsmedchemlett.5b00138

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-l-yOmethyl)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.

引用

页码：888 / 893

页数：11

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