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

  • J Med Chem. 2022 Dec 28. doi: 10.1021/acs.jmedchem.2c01452.
Hongfeng Gu  1 ,  Wenxin Yan  2 ,  Yong Wang  2 ,  Wenbo Xu  2 ,  Lei Huang  2 ,  Jieping Yang  2 ,  Bingxin Zhai  2 ,  Hong Wang  3 ,  Yupei Su  3 ,  Qihua Zhu  2 ,  Beibei Liu  2 ,  Haiping Hao  1  3 ,  Yi Zou  2 ,  Yungen Xu  1  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.
  • 3. Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 211198, China.
PMID: 36576395 DOI: 10.1021/acs.jmedchem.2c01452
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 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.

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