Discovery and Optimization of Potent and Highly Selective PARP14 Inhibitors for the Treatment of Atopic Dermatitis

  • J Med Chem. 2025 May 8;68(9):9755-9776. doi: 10.1021/acs.jmedchem.5c00564.
Shiqi Wu  1  2 ,  Xiaorong Zeng  1 ,  Jing Liu  1 ,  Kaiyuan Cong  1 ,  Shaoxue Lou  1 ,  Ziyue Li  1 ,  Ping Wei  3 ,  Li Shao  3 ,  Yaoyao Zhang  1 ,  Le Qu  1 ,  Tizhi Wu  1 ,  Hongfeng Gu  1 ,  Yan Zhao  3 ,  Zhaoxing Chu  3 ,  Qihua Zhu  1 ,  Guangwei He  3 ,  Yi Zou  1 ,  Yungen Xu  1  2
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
  • 3. Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei 230601, P. R. China.
PMID: 40239060 DOI: 10.1021/acs.jmedchem.5c00564
Abstract

Atopic dermatitis (AD) is a chronic, recurrent, and inflammatory skin condition that remains challenging to treat effectively and safely with current therapies. Recent studies by multiple independent research groups have demonstrated that poly(ADP-ribose) polymerase 14 (PARP14) has been implicated in the progression of inflammatory diseases through its regulation of the Th2 and Th17 signaling pathways, leading to the identification of PARP14 as a promising therapeutic target. Herein, we report the discovery of a novel PARP14 Inhibitor Q22 with exceptional inhibitory activity against PARP14 (IC50 = 5.52 nM), high selectivity toward PARP14, favorable pharmacokinetic properties, and a robust in vivo safety profile. Notably, compared to positive control RBN-3143, Q22 showed significant therapeutic efficacy in a dinitrochlorobenzene (DNCB)-induced AD mouse model by markedly reducing the expression of key AD-associated inflammatory cytokines, including IL-4, IL-13, and IL-17A. These findings suggest that Q22 holds considerable promise as a PARP14 Inhibitor for AD treatment.

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