Discovery of Orally Bioavailable N-Benzylpiperidinol Derivatives as Potent and Selective USP7 Inhibitors with In Vivo Antitumor Immunity Activity against Colon Cancer,Journal of Medicinal Chemistry

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Discovery of Orally Bioavailable N-Benzylpiperidinol Derivatives as Potent and Selective USP7 Inhibitors with In Vivo Antitumor Immunity Activity against Colon Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-12-01 , DOI: 10.1021/acs.jmedchem.2c01444
Xing Li ₁ , Shanlin Yang ₁ , Honghan Zhang ₁ , Xipeng Liu ₁ , Yuchen Gao ₁ , Yuqi Chen ₁ , Liu Liu ₁ , Dalin Wang ₁ , Zijiang Liang ₁ , Shengjie Liu ₁ , Liang Dai _{1,

2} , Qinglong Xu ₁ , Haoliang Yuan _{1,

2} , Caiping Chen _{1,

2} , Hongbin Sun _{1,

2,

3} , Xiaoan Wen _{1,

2,

3}

Affiliation

USP7 emerges as a potential therapeutic target for cancers, as it plays an important role in the development of tumorigenesis by stabilizing multiple cancer-relevant proteins. Nevertheless, the discovery of drug-like USP7 inhibitors remains challenging. Herein, we report a series of N-benzylpiperidinol derivatives as potent and selective USP7 inhibitors (e.g., X20 and X26: IC₅₀ = 7.6 and 8.2 nM), whose binding modes were revealed by crystallographic studies to be distinct from the known N-acylpiperidinol USP7 inhibitors. Among them, X36 with good oral PK profiles (rat: F = 40.8% and T_1/2 = 3.5 h) exhibited significant antitumor efficacy in the MC38 colon cancer syngeneic mouse model, at least partly through upregulating the tumor infiltration of CD8⁺ T, NK, and NKT cells and downregulating that of Tregs and MDSCs. These findings may further pave the way for the development of USP7 inhibitors as novel cancer immunotherapy drugs.

中文翻译：

发现口服生物可利用的 N-苄基哌啶醇衍生物作为有效和选择性的 USP7 抑制剂，具有针对结肠癌的体内抗肿瘤免疫活性

USP7 成为癌症的潜在治疗靶点，因为它通过稳定多种癌症相关蛋白在肿瘤发生的发展中发挥重要作用。然而，类药物 USP7 抑制剂的发现仍然具有挑战性。在此，我们报告了一系列作为有效和选择性 USP7 抑制剂的N -苄基哌啶醇衍生物（例如， X20和X26：IC ₅₀ = 7.6 和 8.2 nM），晶体学研究表明其结合模式不同于已知的N -酰基哌啶醇USP7 抑制剂。其中，X36具有良好的口服 PK 曲线（大鼠：F = 40.8% 和T _1/2= 3.5 h) 在 MC38 结肠癌同基因小鼠模型中表现出显着的抗肿瘤功效，至少部分是通过上调 CD8 ⁺ T、NK 和 NKT 细胞的肿瘤浸润以及下调 Treg 和 MDSC 的肿瘤浸润。这些发现可能进一步为开发 USP7 抑制剂作为新型癌症免疫治疗药物铺平道路。

更新日期：2022-12-01

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