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

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.