2. Academic Validation
  3. Discovery of the Potent and Highly Selective PARP7 Inhibitor as a Novel Immunotherapeutic Agent for Tumors

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

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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