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
  • 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.
PMID: 39316753 DOI: 10.1021/acschembio.4c00397
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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