Discovery of the Potent and Highly Selective PARP7 Inhibitor as a Novel Immunotherapeutic Agent for Tumors.

PARP7, a polyadenosine diphosphate-ribose polymerase, has been identified as a negative regulator in type I interferon (IFN) signaling. An overexpression of PARP7 is typically found in a wide range of cancers and can lead to the suppression of type I IFN signaling and innate immune response. Herein, we describe the discovery of compound , a novel PARP7 inhibitor with high inhibitory potency (IC = 7.6 nM) and selectivity for PARP7 over other PARPs. Especially, has excellent pharmacokinetic properties and low toxicity in mice and exhibits significantly stronger antitumor potency (TGI: 67%) than (TGI: 30%) without the addition of 1-aminobenzotriazole (a nonselective and irreversible inhibitor of cytochrome P450) in CT26 syngeneic mouse models. Our findings reveal that mainly acts as an immune activator through PARP7 inhibition in the tumor microenvironment, which highlights the potential advantages of as a tumor immunotherapeutic agent.