Gu Hongfeng, Yan Wenxin, Wang Yong, Xu Wenbo, Huang Lei, Yang Jieping, Zhai Bingxin, Wang Hong, Su Yupei, Zhu Qihua, Liu Beibei, Hao Haiping, Zou Yi, Xu Yungen
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.
J Med Chem. 2023 Jan 12;66(1):473-490. doi: 10.1021/acs.jmedchem.2c01452. Epub 2022 Dec 28.
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 , a novel PARP7 inhibitor with high inhibitory potency (IC = 7.6 nM) and selectivity for PARP7 over other PARPs. Especially, has excellent pharmacokinetic properties and low toxicity in mice and exhibits significantly stronger antitumor potency (TGI: 67%) than (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 mainly acts as an immune activator through PARP7 inhibition in the tumor microenvironment, which highlights the potential advantages of as a tumor immunotherapeutic agent.
聚腺苷二磷酸核糖聚合酶7（PARP7）已被确定为I型干扰素（IFN）信号传导的负调节因子。PARP7的过表达通常在多种癌症中被发现，并可导致I型IFN信号传导和先天免疫反应受到抑制。在此，我们描述了化合物的发现，它是一种新型PARP7抑制剂，对PARP7具有高抑制效力（IC = 7.6 nM），且对其他PARP具有选择性。特别是，该化合物在小鼠中具有优异的药代动力学特性和低毒性，并且在CT26同基因小鼠模型中，在不添加1-氨基苯并三唑（一种细胞色素P450的非选择性不可逆抑制剂）的情况下，其抗肿瘤效力（TGI：67%）比另一种药物（TGI：30%）显著更强。我们的研究结果表明，该化合物主要通过抑制肿瘤微环境中的PARP7来充当免疫激活剂，这突出了其作为肿瘤免疫治疗药物的潜在优势。
