Cellular Activity of New Small Molecule Protein Arginine Deiminase 3 (PAD3) Inhibitors

Haya Jamali; Hasan A. Khan; Caroline C. Tjin; Jonathan A. Ellman

doi:10.1021/acsmedchemlett.6b00215

Cellular Activity of New Small Molecule Protein Arginine Deiminase 3 (PAD3) Inhibitors

Haya Jamali, Hasan A. Khan, Caroline C. Tjin, Jonathan A. Ellman

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

19 Scopus citations

Abstract

The protein arginine deiminases (PADs) catalyze the post-translational deimination of arginine side chains. Multiple PAD isozymes have been characterized, and abnormal PAD activity has been associated with several human disease states. PAD3 has been characterized as a modulator of cell growth via apoptosis inducing factor and has been implicated in the neurodegenerative response to spinal cord injury. Here, we describe the design, synthesis, and evaluation of conformationally constrained versions of the potent and selective PAD3 inhibitor 2. The cell activity of representative inhibitors in this series was also demonstrated for the first time by rescue of thapsigargin-induced cell death in PAD3-expressing HEK293T cells.

Original language	English
Pages (from-to)	847-851
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	7
Issue number	9
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00215
State	Published - 8 Sep 2016
Externally published	Yes

Keywords

Protein arginine deiminases
apoptosis inducing factor
small molecule inhibitor
spinal cord injury

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10.1021/acsmedchemlett.6b00215

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abstract = "The protein arginine deiminases (PADs) catalyze the post-translational deimination of arginine side chains. Multiple PAD isozymes have been characterized, and abnormal PAD activity has been associated with several human disease states. PAD3 has been characterized as a modulator of cell growth via apoptosis inducing factor and has been implicated in the neurodegenerative response to spinal cord injury. Here, we describe the design, synthesis, and evaluation of conformationally constrained versions of the potent and selective PAD3 inhibitor 2. The cell activity of representative inhibitors in this series was also demonstrated for the first time by rescue of thapsigargin-induced cell death in PAD3-expressing HEK293T cells.",

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AB - The protein arginine deiminases (PADs) catalyze the post-translational deimination of arginine side chains. Multiple PAD isozymes have been characterized, and abnormal PAD activity has been associated with several human disease states. PAD3 has been characterized as a modulator of cell growth via apoptosis inducing factor and has been implicated in the neurodegenerative response to spinal cord injury. Here, we describe the design, synthesis, and evaluation of conformationally constrained versions of the potent and selective PAD3 inhibitor 2. The cell activity of representative inhibitors in this series was also demonstrated for the first time by rescue of thapsigargin-induced cell death in PAD3-expressing HEK293T cells.

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Cellular Activity of New Small Molecule Protein Arginine Deiminase 3 (PAD3) Inhibitors

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Keywords

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