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