Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Bioorg Chem. 2021 Sep;114:105034. doi: 10.1016/j.bioorg.2021.105034. Epub 2021 May 30.
Blockade of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signalling pathway is a promising tumour immunotherapeutic approach, and small molecule drugs have more advantages than monoclonal antibody macromolecules in clinical applications. Therefore, a series of 1-methyl-1H-pyrazolo[4,3-b]pyridine derivatives as PD-1/PD-L1 interaction novel small-molecule inhibitors were designed employing a ring fusion strategy. The inhibitory activity of compounds was evaluated by the HTRF assay, among which D38 was identified as the most potent PD-1/PD-L1 interaction inhibitor with an IC value of 9.6 nM. Furthermore, D38 exhibited prominent inhibitory activity against the PD-1/PD-L1 interaction with an EC value of 1.61 μM in a coculture model of PD-L1/TCR activator-expressing CHO cells and PD-1-expressing Jurkat cells. In addition, the preliminary structure-activity relationships (SARs) of compounds were elucidated, and the binding mode of D38 with the PD-L1 dimer was analysed by molecular docking. Overall, D38 could be employed as a prospective lead compound of PD-1/PD-L1 interaction inhibitors for further development.
阻断程序性细胞死亡蛋白-1（PD-1）/程序性细胞死亡配体 1（PD-L1）信号通路是一种很有前途的肿瘤免疫治疗方法，小分子药物在临床应用中比单克隆抗体大分子具有更多优势。因此，我们采用环融合策略设计了一系列 1-甲基-1H-吡唑并[4,3-b]吡啶衍生物作为 PD-1/PD-L1 相互作用的新型小分子抑制剂。通过 HTRF 测定法评估了化合物的抑制活性，其中 D38 被鉴定为最有效的 PD-1/PD-L1 相互作用抑制剂，IC 值为 9.6 nM。此外，D38 在 PD-L1/TCR 激活剂表达 CHO 细胞和 PD-1 表达 Jurkat 细胞共培养模型中对 PD-1/PD-L1 相互作用具有显著的抑制活性，EC 值为 1.61 μM。此外，还阐明了化合物的初步构效关系（SAR），并通过分子对接分析了 D38 与 PD-L1 二聚体的结合模式。总之，D38 可以作为 PD-1/PD-L1 相互作用抑制剂的有前途的先导化合物，用于进一步开发。
