Damfo Shymaa, Alkayyal Almohanad A, Mahmoud Ahmad Bakur
Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Madinah, Kingdom of Saudi Arabia.
Health and Life Research Center, Taibah University, Madinah, Kingdom of Saudi Arabia.
Anticancer Res. 2025 Sep;45(9):3727-3735. doi: 10.21873/anticanres.17733.
BACKGROUND/AIM: Research into PD-L1 is critical in the development of small-molecule anti-cancer drugs. The current chemical compounds that bind to PD-1/PD-L1 exhibit lower efficacy than clinically relevant monoclonal antibodies, necessitating the need for new inhibitors. The aim of this study was to identify and characterise small-molecule inhibitors of PD-1/PD-L1 interaction.
In this study, 1,900 compounds were screened against the PDL-1 target to identify binders using the ICM program. Virtual characterization by SwissADME of chemical scaffolds exhibiting high binding affinity to PD-L1 was performed. This was followed by the evaluation of the compounds for their PD-L1/PD-1 inhibitory activity in an ELISA assay, compared to the control.
Analysis of the inhibition of the PD-L1 and PD-1 interaction revealed significant inhibition of the interaction with four compounds (Compound 3; X86577), (Compound 4; X02079), (Compound 6; X53550), and (Compound 9; X14474) compared to the anti-PD-1 neutralizing antibody.
The findings present optimised small-molecule inhibitors targeting the PD-1/PD-L1 pathway, which could serve as effective immune checkpoint inhibitors. This work provides valuable insight into therapeutic solutions in addressing unmet medical needs in the oncology field.
背景/目的：PD-L1研究对于小分子抗癌药物的开发至关重要。目前与PD-1/PD-L1结合的化合物疗效低于临床相关单克隆抗体，因此需要新的抑制剂。本研究旨在鉴定和表征PD-1/PD-L1相互作用的小分子抑制剂。
在本研究中，使用ICM程序针对PDL-1靶点筛选了1900种化合物以鉴定结合剂。通过SwissADME对与PD-L1表现出高结合亲和力的化学支架进行虚拟表征。随后在ELISA试验中评估这些化合物对PD-L1/PD-1的抑制活性，并与对照进行比较。
与抗PD-1中和抗体相比，对PD-L1和PD-1相互作用抑制的分析显示，四种化合物（化合物3；X86577）、（化合物4；X02079）、（化合物6；X53550）和（化合物9；X14474）对该相互作用有显著抑制作用。
研究结果展示了针对PD-1/PD-L1途径的优化小分子抑制剂，其可作为有效的免疫检查点抑制剂。这项工作为解决肿瘤学领域未满足的医疗需求的治疗方案提供了有价值的见解。
