Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage,Journal of Medicinal Chemistry

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Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-11 , DOI: 10.1021/acs.jmedchem.1c01422
Zilan Song _{1,

2,

3,

4} , Bo Liu ₂ , Xia Peng ₃ , Wangting Gu ₁ , Yiming Sun ₂ , Li Xing ₁ , Yi Xu ₅ , Meiyu Geng _{2,

3,

4} , Jing Ai _{2,

4} , Ao Zhang _{1,

2,

3,

4,

6}

Affiliation

Blockade of immune checkpoint PD-1/PD-L1 has been a promising anticancer strategy; however, clinically available PD-1/PD-L1 small-molecule inhibitors are lacking. In view of the high potency of compound 2 (BMS-1002), structural fine tuning of the methoxy linkage together with diverse modification in the solvent interaction region was conducted. A series of novel derivatives featuring a difluoromethyleneoxy linkage were designed. Compound 43 was identified as the most promising PD-1/PD-L1 inhibitor with an IC₅₀ value of 10.2 nM in the HTRF assay. This compound is capable of promoting CD8⁺ T cell activation through inhibiting PD-1/PD-L1 cellular signaling. Moreover, in the Hepa1-6 syngeneic mouse model, administration of compound 43 at 1 mg/kg dosage promoted CD8⁺ T cell activation and delayed the tumor growth with good tolerance. Notably, the tumor in one mouse of the compound 43-treated group was completely regressed. These results indicate that compound 43 is a promising candidate worthy of further investigation.

中文翻译：

具有独特二氟亚甲氧基键的含联芳基 PD-1/PD-L1 相互作用抑制剂的设计、合成和药理学评价

阻断免疫检查点PD-1/PD-L1一直是一种很有前景的抗癌策略；然而，缺乏临床可用的PD-1/PD-L1小分子抑制剂。鉴于化合物2 (BMS-1002) 的高效力，进行了甲氧基键的结构微调以及溶剂相互作用区域的多种修饰。设计了一系列具有二氟亚甲氧基键的新型衍生物。化合物43被鉴定为最有希望的 PD-1/PD-L1 抑制剂，在 HTRF 测定中其 IC ₅₀值为 10.2 nM。该化合物能够通过抑制 PD-1/PD-L1 细胞信号传导来促进 CD8 ⁺ T 细胞活化。此外，在 Hepa1-6 同系小鼠模型中，给予化合物43在 1 mg/kg 剂量下促进 CD8 ⁺ T 细胞活化并以良好的耐受性延缓肿瘤生长。值得注意的是，化合物43治疗组的一只小鼠中的肿瘤完全消退。这些结果表明化合物43是一种有前途的候选物，值得进一步研究。

更新日期：2021-11-25

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