Discovery of Highly Selective PARP7 Inhibitors with a Novel Scaffold for Cancer Immunotherapy

PARP7 plays a crucial role in cancer immunity. The inhibition
of
PARP7 has shown potential in boosting the immune response against
cancer, making it an attractive target for cancer immunotherapy. Herein,
we employed a rigid constraint strategy (reduction in molecular flexibility)
to design and synthesize a series of novel indazole-7-carboxamide
derivatives based on the structure of RBN-2397. Among these derivatives, (S)-XY-05 was identified as
the most promising PARP7 inhibitor (IC50: 4.5 nM). Additionally, (S)-XY-05 showed enhanced selectivity
toward PARP7 and improved pharmacokinetic properties (oral bioavailability:
94.60%) compared with RBN-2397 (oral bioavailability: 25.67%). In
the CT26 syngeneic mouse model, monotherapy with (S)-XY-05 displayed a strong antitumor effect
(TGI: 83%) by activating T-cell-mediated immunity within the tumor
microenvironment. Collectively, we confirmed that (S)-XY-05 has profound effects on tumor immunity,
which paves the way for future studies of PARP7 inhibitors that could
be utilized in cancer immunotherapy.