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

  • J Med Chem. 2023 Dec 7. doi: 10.1021/acs.jmedchem.3c01764.
Hongfeng Gu  1  2 ,  Wenxin Yan  2 ,  Jieping Yang  2 ,  Beibei Liu  2 ,  Xiaolin Zhao  2 ,  Hongxia Wang  2 ,  Wenbo Xu  2 ,  Chenghao Wang  2 ,  Yang Chen  2 ,  Qiuyi Dong  2 ,  Qihua Zhu  2 ,  Yungen Xu  1  2 ,  Yi Zou  2
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
PMID: 38059836 DOI: 10.1021/acs.jmedchem.3c01764
Abstract

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.

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