Javed Sadique A, Najmi Asim, Ahsan Waquar, Zoghebi Khalid
Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia.
Front Immunol. 2024 Apr 10;15:1383456. doi: 10.3389/fimmu.2024.1383456. eCollection 2024.
The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised anticancer immunity. PD-1/PD-L-1 interaction blockade shown remarkable clinical success in various cancer immunotherapies. To date, most PD-1/PD-L-1 blockers approved for clinical use are monoclonal antibodies (mAbs); however, their therapeutic use are limited owing to poor clinical responses in a proportion of patients. mAbs also displayed low tumor penetration, steep production costs, and incidences of immune-related side effects. This strongly indicates the importance of developing novel inhibitors as cancer immunotherapeutic agents. Recently, advancements in the small molecule-based inhibitors (SMIs) that directly block the PD-1/PD-L-1 axis gained attention from the scientific community involved in cancer research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, low cost, greater cell penetration, and possibility of oral administration. Currently, several SMIs are in development pipeline as potential therapeutics for cancer immunotherapy. To develop new SMIs, a wide range of structural scaffolds have been explored with excellent outcomes; biphenyl-based scaffolds are most studied. In this review, we analyzed the development of mAbs and SMIs targeting PD-1/PD-L-1 axis for cancer treatment. Altogether, the present review delves into the problems related to mAbs use and a detailed discussion on the development and current status of SMIs. This article may provide a comprehensive guide to medicinal chemists regarding the potential structural scaffolds required for PD-1/PD-L-1 interaction inhibition.
程序性死亡-1受体（PD-1）起着T细胞制动的作用，它与配体-1（PD-L-1）的相互作用会干扰T细胞受体的信号转导。这会导致肿瘤微环境中T细胞的存活、增殖和活性受到抑制，从而削弱抗癌免疫力。在各种癌症免疫疗法中，PD-1/PD-L-1相互作用阻断已显示出显著的临床成功。迄今为止，大多数被批准用于临床的PD-1/PD-L-1阻断剂都是单克隆抗体（mAb）；然而，由于一部分患者临床反应不佳，它们的治疗用途受到限制。mAb还表现出肿瘤穿透力低、生产成本高以及免疫相关副作用的发生率。这有力地表明了开发新型抑制剂作为癌症免疫治疗药物的重要性。最近，直接阻断PD-1/PD-L-1轴的基于小分子的抑制剂（SMI）的进展引起了参与癌症研究的科学界的关注。SMI相对于mAb显示出某些优势，包括更长的半衰期、低成本、更高的细胞穿透力以及口服给药的可能性。目前，有几种SMI正在作为癌症免疫治疗的潜在疗法进行研发。为了开发新的SMI，已经探索了多种结构支架并取得了优异的成果；基于联苯的支架研究最多。在这篇综述中，我们分析了靶向PD-1/PD-L-1轴用于癌症治疗的mAb和SMI的发展。总之，本综述深入探讨了与mAb使用相关的问题以及对SMI的发展和现状的详细讨论。本文可能会为药物化学家提供关于抑制PD-1/PD-L-1相互作用所需潜在结构支架的全面指南。
