Discovery of Pyrazole-Containing 4-Arylindolines as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-08 DOI:10.1021/acsmedchemlett.5c00423

Wensong Deng, Yuan Yang, Tairen Zhou, Xuanchi Zhu, Bing Xu, Xiaoyao Zhao, Kun Huang, Yanqi Jin, Lihui Wang* and Mingze Qin*,

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Abstract

The development of small-molecule inhibitors targeting the programmed cell death-1(PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a promising strategy in tumor immunotherapy. In this study, a series of 4-arylindoline derivatives containing a pyrazole moiety were designed and synthesized through a medicinal chemistry campaign based on compound 1, a potent immunomodulator previously reported by our group. Among these, compound J29 was identified as the most promising inhibitor, exhibiting an IC₅₀ value of 5.5 nM against the PD-1/PD-L1 interaction in a biochemical assay. In coculture models of tumor cells and T cells, J29 effectively promoted T-cell proliferation and restored their ability to kill tumor cells. Moreover, J29 showed significantly improved metabolic stability in human liver microsomes (HLMs) compared with compound 1. These findings indicate that J29 represents a promising lead compound for the further development of small-molecule PD-1/PD-L1 interaction inhibitors.

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含吡唑的4-芳基喹啉作为程序性细胞死亡-1/程序性细胞死亡-配体-1相互作用的有效小分子抑制剂的发现

靶向程序性细胞死亡-1(PD-1)/程序性细胞死亡-配体-1（PD-L1）相互作用的小分子抑制剂的开发已成为肿瘤免疫治疗的一种有前景的策略。在这项研究中，我们设计并合成了一系列含有吡唑片段的4-芳唑啉衍生物，这些衍生物以化合物1为基础，通过药物化学运动，我们的团队之前报道过一种有效的免疫调节剂。其中，化合物J29被认为是最有希望的抑制剂，在生化实验中对PD-1/PD-L1相互作用的IC50值为5.5 nM。在肿瘤细胞与T细胞共培养模型中，J29有效促进T细胞增殖，恢复T细胞杀伤肿瘤细胞的能力。此外，与化合物1相比，J29显著改善了人肝微粒体（HLMs）的代谢稳定性。这些发现表明J29为进一步开发小分子PD-1/PD-L1相互作用抑制剂提供了一个有希望的先导化合物。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.