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.