Discovery of highly potent PARP7 inhibitors for cancer immunotherapy

  • Bioorg Chem. 2024 Jul:148:107469. doi: 10.1016/j.bioorg.2024.107469.
Jieping Yang  1 ,  Beibei Liu  1 ,  Wenxin Yan  1 ,  Xiaolin Zhao  1 ,  Chenghao Wang  1 ,  Qihua Zhu  1 ,  Yi Zou  2 ,  Yungen Xu  3 ,  Hongfeng Gu  4
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
  • 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
PMID: 38781669 DOI: 10.1016/j.bioorg.2024.107469
Abstract

PARP7 has been proven to play an important role in immunity. Substantial upregulation of PARP7 is observed in numerous cancerous cell types, consequently resulting in the inhibition of type Ⅰ interferon signaling pathways. Therefore, inhibiting the activity of PARP7 can enhance type Ⅰ interferon signaling to exert an anti-tumor immune response. In this study, we reported the identification of a newly found PARP7 Inhibitor (XLY-1) with higher inhibitory activity (IC50 = 0.6 nM) than that of RBN-2397 (IC50 = 6.0 nM). Additionally, XYL-1 displayed weak inhibitory activity on PARP1 (IC50 > 1.0 μM). Mechanism studies showed that XYL-1 could enhance the type Ⅰ interferon signaling in vitro. Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI: 76.5 %) and related experiments showed that XYL-1 could restore type Ⅰ interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing Cancer Immunotherapy agents.

Keywords
Anticancer studies; IFN-β; Immunotherapy; Mono-PARP; PARP1; PARP7; RBN-2397; TBK1.
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