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

Caroline Chandra Tjin; Rebecca F. Wissner; Haya Jamali; Alanna Schepartz; Jonathan A. Ellman

doi:10.1021/acsmedchemlett.8b00283

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

Caroline Chandra Tjin, Rebecca F. Wissner, Haya Jamali, Alanna Schepartz, Jonathan A. Ellman

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1013-1018
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00283
State	Published - 11 Oct 2018
Externally published	Yes

Keywords

Protein arginine deiminase
citrullination
inflammatory disease
mechanism-based inhibitor
rheumatoid arthritis

Access to Document

10.1021/acsmedchemlett.8b00283

Cite this

@article{9f231a0537da4fc4b5e62b697601b810,

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

abstract = "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.",

keywords = "Protein arginine deiminase, citrullination, inflammatory disease, mechanism-based inhibitor, rheumatoid arthritis",

author = "Tjin, {Caroline Chandra} and Wissner, {Rebecca F.} and Haya Jamali and Alanna Schepartz and Ellman, {Jonathan A.}",

note = "Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = oct,

day = "11",

doi = "10.1021/acsmedchemlett.8b00283",

language = "English",

volume = "9",

pages = "1013--1018",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "10",

}

TY - JOUR

T1 - Synthesis and Biological Evaluation of an Indazole-Based Selective Protein Arginine Deiminase 4 (PAD4) Inhibitor

AU - Tjin, Caroline Chandra

AU - Wissner, Rebecca F.

AU - Jamali, Haya

AU - Schepartz, Alanna

AU - Ellman, Jonathan A.

PY - 2018/10/11

Y1 - 2018/10/11

N2 - 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.

AB - 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.

KW - Protein arginine deiminase

KW - citrullination

KW - inflammatory disease

KW - mechanism-based inhibitor

KW - rheumatoid arthritis

UR - http://www.scopus.com/inward/record.url?scp=85053931100&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.8b00283

DO - 10.1021/acsmedchemlett.8b00283

M3 - Article

AN - SCOPUS:85053931100

SN - 1948-5875

VL - 9

SP - 1013

EP - 1018

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 10

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this