1. Academic Validation
  2. Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism

Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism

  • ACS Chem Biol. 2024 Oct 18;19(10):2186-2197. doi: 10.1021/acschembio.4c00397.
Laura J Byrnes 1 Won Young Choi 1 Paul Balbo 2 Mary Ellen Banker 1 Jeanne Chang 1 Shi Chen 3 Xuemin Cheng 3 Yang Cong 1 Jeff Culp 1 Hongxia Di 3 Matt Griffor 1 Justin Hall 1 Xiaoyun Meng 3 Barry Morgan 3 James J Mousseau 1 Jennifer Nicki 1 Thomas O'Connell 1 Simeon Ramsey 2 Alex Shaginian 3 Suman Shanker 1 John Trujillo 1 Jinqiao Wan 3 Fabien Vincent 1 Stephen W Wright 1 Felix Vajdos 1
Affiliations

Affiliations

  • 1 Pfizer Worldwide Research and Development, Eastern Pt. Rd, Groton, Connecticut 06340-5146, United States.
  • 2 Pfizer Worldwide Research and Development, 1 Portland St., Cambridge, Massachusetts 02139, United States.
  • 3 Hitgen Inc., Building C2, NO.8, Huigu first East Road, Tianfu International Bio-Town, Shuangliu District, Chengdu City, Sichuan Province 610041, P.R. China.
Abstract

Peptidyl arginine deiminases (PADs) are important Enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library. The biochemical and biophysical characterization of this inhibitor and two noninhibitory Binders indicated a novel, CA2+ competitive mechanism of inhibition. This was confirmed via X-ray crystallographic analysis. Finally, we demonstrate that this inhibitor selectively inhibits PAD2 in a cellular context.

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