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ACS Med Chem Lett. 2018 Sep 14;9(10):1013-1018. doi: 10.1021/acsmedchemlett.8b00283. eCollection 2018 Oct 11.

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

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Department of Chemistry and Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States.


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.

[Available on 2019-10-11]

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