Syntheses, Biological Evaluations, and Mechanistic Studies of Benzo[c][1,2,5]oxadiazole Derivatives as Potent PD-L1 Inhibitors with In Vivo Antitumor Activity,Journal of Medicinal Chemistry

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Syntheses, Biological Evaluations, and Mechanistic Studies of Benzo[c][1,2,5]oxadiazole Derivatives as Potent PD-L1 Inhibitors with In Vivo Antitumor Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-06-11 , DOI: 10.1021/acs.jmedchem.1c00392
Liu Liu ₁ , Zhiying Yao ₁ , Shijun Wang ₁ , Tao Xie ₁ , Guoqing Wu ₁ , Honghan Zhang ₁ , Pu Zhang ₂ , Yaojun Wu ₂ , Haoliang Yuan ₁ , Hongbin Sun _{1,

3}

Affiliation

A series of novel benzo[c][1,2,5]oxadiazole derivatives were designed, synthesized, and biologically evaluated as inhibitors of PD-L1. Among them, compound L7 exhibited 1.8 nM IC₅₀ value in a homogeneous time-resolved fluorescence (HTRF) assay, which was 20-fold more potent than the lead compound BMS-1016. In the surface plasmon resonance (SPR) assay, L7 bound to human PD-L1 (hPD-L1) with a K_D value of 3.34 nM, without showing any binding to hPD-1. In the cell-based coculture assay, L7 blocked PD-1/PD-L1 interaction with an EC₅₀ value of 375 nM, while BMS-1016 had an EC₅₀ value of 2075 nM. Moreover, compound L24, an ester prodrug of L7, was orally bioavailable and displayed significant antitumor effects in tumor models of syngeneic and PD-L1 humanized mice. Mechanistically, L24 exhibited significant in vivo antitumor effects probably through promoting antitumor immunity. Together, this series of benzoxadiazole PD-L1 inhibitors holds promise for tumor immunotherapy. Preclinical trials with selected compounds are ongoing in our laboratory.

中文翻译：

具有体内抗肿瘤活性的强效 PD-L1 抑制剂苯并[c][1,2,5]恶二唑衍生物的合成、生物学评价和机理研究

设计、合成了一系列新型苯并[ c ][1,2,5]恶二唑衍生物，并对其作为PD-L1抑制剂进行了生物学评价。其中，化合物L7在均相时间分辨荧光（HTRF）测定中表现出1.8 nM IC ₅₀值，其效力比先导化合物BMS-1016强20倍。在表面等离子共振 (SPR) 测定中， L7与人 PD-L1 (hPD-L1) 结合， KD_值为3.34 nM，但未显示与 hPD-1 的任何结合。在基于细胞的共培养测定中， L7阻断 PD-1/PD-L1 相互作用，EC ₅₀值为 375 nM，而BMS-1016的 EC ₅₀值为 2075 nM。此外，化合物L24 （ L7的酯前药）具有口服生物利用度，并且在同基因小鼠和PD-L1人源化小鼠的肿瘤模型中显示出显着的抗肿瘤作用。从机制上讲， L24可能通过促进抗肿瘤免疫而表现出显着的体内抗肿瘤作用。总之，这一系列苯并恶二唑 PD-L1 抑制剂为肿瘤免疫治疗带来了希望。我们的实验室正在进行选定化合物的临床前试验。

更新日期：2021-06-24

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