The PARP14 inhibitor RBN-3143 suppresses lung inflammation in preclinical models

PARP14 is an enzyme of the ADP-ribosyltransferase (ART) family which modifies its substrates by ADP-ribosylation. Published work suggests that PARP14 promotes Th2/Th17 signaling in immune cells by amplifying STAT6- and STAT3-driven transcription, thereby modulating inflammation. PARP14 expression is promoted by interferons and TLR agonists in many cell types, including immune and epithelial cells. Tissue analysis from patients with inflammation of the lung, skin, and colon shows increased PARP14 expression in immune and structural cells of the affected organs, compared to normal tissues. We hypothesize that increased PARP14 expression fosters tissue inflammation, and PARP14 inhibition is a new treatment strategy for inflammatory disease. We developed RBN-3143, an NAD+-competitive catalytic inhibitor of PARP14 with nanomolar potency against PARP14 and more than 300-fold selectivity over other ARTs. RBN-3143 is well-tolerated in preclinical studies. In a mouse model of severe, steroid-resistant asthma RBN-3143 broadly suppressed disease phenotypes such as airway mucus, serum-IgE levels, and the accumulation of immune cells and inflammatory cytokines in the BALF. Notably, RBN-3143 also suppressed the accumulation of alarmins TSLP, IL-33, and IL-25, while anti-IL-5 therapy did not. RBN-3143 also demonstrated efficacy in other mouse models of inflammatory disease of the lung, skin, and colon. Our data suggests that PARP14 is a promising drug target for Th2/Th17-driven inflammation. RBN-3143 is currently in a Phase I clinical trial (NCT05215808) in healthy volunteers. It is the first small molecule inhibitor of PARP14 entering clinical trials and this abstract is the first public disclosure of the compound.