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

Abstract

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 <b>I-1</b>, a novel PARP7 inhibitor with high inhibitory potency (IC₅₀ = 7.6 nM) and selectivity for PARP7 over other PARPs. Especially, <b>I-1</b> has excellent pharmacokinetic properties and low toxicity in mice and exhibits significantly stronger <i>in vivo</i> antitumor potency (TGI: 67%) than <b>RBN-2397</b> (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 <b>I-1</b> mainly acts as an immune activator through PARP7 inhibition in the tumor microenvironment, which highlights the potential advantages of <b>I-1</b> as a tumor immunotherapeutic agent.