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

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.