Synthesis and Biological Evaluation of an Indazole-Based Selective Protein Arginine Deiminase 4 (PAD4) Inhibitor

被引：16

作者：

Tjin, Caroline Chandra ^{[1
]}

Wissner, Rebecca F. ^{[1
]}

Jamali, Haya ^{[1
]}

Schepartz, Alanna ^{[1
,2
]}

Ellman, Jonathan A. ^{[1
]}

机构：

[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA

[2] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 10期

关键词：

Protein arginine deiminase; mechanism-based inhibitor; rheumatoid arthritis; inflammatory disease; citrullination; EPIGENETIC REGULATION; RHEUMATOID-ARTHRITIS; CITRULLINATION; METHYLATION; NEUTROPHILS; ACTIVATION; EXPRESSION; TISSUES; DESIGN; BLOOD;

D O I：

10.1021/acsmedchemlett.8b00283

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Protein arginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the conversion of arginine to citrulline within target proteins. Dysregulation of PAD4 has been implicated in a number of human diseases, including rheumatoid arthritis and other inflammatory diseases as well as cancer. In this study, we report on the design, synthesis, and evaluation of a new class of haloacetamidine-based compounds as potential PAD4 inhibitors. Specifically, we describe the identification of 4,5,6-trichloroindazole 24 as a highly potent PAD4 inhibitor that displays >10-fold selectivity for PAD4 over PAD3 and >50-fold over PAD1 and PAD2. The efficacy of this compound in cells was determined by measuring the inhibition of PAD4-mediated H4 citrullination in HL-60 granulocytes.

引用

页码：1013 / 1018

页数：11

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