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.

Citation

Hongfeng Gu, Wenxin Yan, Jieping Yang, Beibei Liu, Xiaolin Zhao, Hongxia Wang, Wenbo Xu, Chenghao Wang, Yang Chen, Qiuyi Dong, Qihua Zhu, Yungen Xu, Yi Zou. Discovery of Highly Selective PARP7 Inhibitors with a Novel Scaffold for Cancer Immunotherapy. Journal of medicinal chemistry. 2024 Feb 08;67(3):1932-1948

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PMID: 38059836

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