2. Academic Validation
  3. Discovery and Optimization of Potent and Highly Selective PARP14 Inhibitors for the Treatment of Atopic Dermatitis

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

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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