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

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z