Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction,European Journal of Medicinal Chemistry

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Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-06-29 , DOI: 10.1016/j.ejmech.2024.116622
Hanxun Wang ₁ , Lanlan Shen ₁ , Lu Chen ₁ , Yinli Gao ₁ , Lanyan Ma ₁ , Wenxiong Lian ₁ , Zhihao Zhang ₁ , Haihan Liu ₁ , Huali Yang ₁ , Jian Wang ₁ , Dongmei Zhao ₁ , Maosheng Cheng ₁

Affiliation

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on and our previous work , a series of compounds with benzo[]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, exhibited the most potent inhibitory activity with an IC value of 2.61 nM. The cellular level assays demonstrated that exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that could interrupt PD-1/PD-L1 interaction with an IC value of 0.88 μM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of and -symmetric small molecule inhibitor . These results suggested that exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation.

中文翻译：

基于苯并[d]异噻唑的针对PD-1/PD-l1相互作用的小分子抑制剂的设计、合成、药理学评价和计算研究

阻断程序性细胞死亡-1（PD-1）/程序性细胞死亡配体1（PD-L1）途径是免疫治疗的一种有吸引力的策略，但小分子PD-1/PD-L1抑制剂的临床应用仍不清楚。本工作在我们前期工作的基础上，设计并合成了一系列以苯并[]异噻唑结构为骨架的化合物。通过均相时间分辨荧光 (HTRF) 测定评估它们对 PD-1/PD-L1 相互作用的抑制活性。其中，表现出最有效的抑制活性，IC 值为 2.61 nM。细胞水平测定表明，其对 Jurkat T 和 MDA-MB-231 表现出低细胞毒性。基于 PD-1 NFAT-Luc Jurkat 细胞和 PD-L1 TCR Activator CHO 细胞的进一步细胞 PD-1/PD-L1 阻断生物测定表明，可以中断 PD-1/PD-L1 相互作用，IC 值为 0.88 μM 。对PD-L1二聚体复合物采用分子对接、分子动力学、MM/GBSA、MM/PBSA、Metadynamics、QM/MM MD等多种计算方法，揭示了对称小分子的结合模式和解离过程。抑制剂。这些结果表明，其作为 PD-1/PD-L1 抑制剂表现出有希望的效力，有待进一步研究。

更新日期：2024-06-29

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