Discovery of Highly Potent Phthalazinone Derivatives as PARP14 Inhibitors: From Structure-Based Virtual Screening to In Vivo Pharmacodynamic Activity

  • J Med Chem. 2026 May 14;69(9):10715-10733. doi: 10.1021/acs.jmedchem.6c00004.
Shiqi Wu  1  2 ,  Kaiyuan Cong  1 ,  Jing Liu  1 ,  Le Qu  1 ,  Xiaorong Zeng  1 ,  Xiangying Kong  1 ,  Ziyue Li  1 ,  Shaoxue Lou  1 ,  Ping Wei  3 ,  Li Shao  3 ,  Hongfeng Gu  1 ,  Yan Zhao  3 ,  Qinlong Xu  3 ,  Zhaoxing Chu  3 ,  Guangwei He  3 ,  Qihua Zhu  1 ,  Yungen Xu  1  2 ,  Yi Zou  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
  • 2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
  • 3. Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei 230601, PR China.
PMID: 42008449 DOI: 10.1021/acs.jmedchem.6c00004
Abstract

PARP14, a pivotal mono-ADP-ribosyltransferase, has been reported to promote the development of inflammatory diseases via IL-4/STAT6/Th2 and IL-6/STAT3/Th17 signaling axes, making it an attractive therapeutic target for related disorders. Herein, we employed structure-based virtual screening and subsequent structural optimization to identify a series of novel PARP14 inhibitors featuring a phthalazinone scaffold. Among them, compound XW-17 exhibited strong PARP14 inhibitory activity (IC50 = 3.03 nM), exceptional selectivity, and robust suppression of PARP14-mediated mono-ADP-ribosylation (MARylation) in cell-based assays. In a dinitrochlorobenzene (DNCB)-induced Atopic Dermatitis (AD)-like mouse model, XW-17 significantly attenuated skin lesions and effectively decreased the expression of key inflammatory factors, including IL-4, IL-13, IgE, and IL-17A, demonstrating superior efficacy compared with RBN-3143 and Upadacitinib. In short, our findings establish XW-17 as a novel and potent PARP14 Inhibitor with promising therapeutic potential against AD.

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