Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, Krakow 30-387, Poland.
Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, Krakow 30-663, Poland.
J Med Chem. 2020 Oct 8;63(19):11271-11285. doi: 10.1021/acs.jmedchem.0c01260. Epub 2020 Sep 23.
Immune checkpoint blockade is one of the most promising strategies of cancer immunotherapy. However, unlike classical targeted therapies, it is currently solely based on expensive monoclonal antibodies, which often inflict immune-related adverse events. Herein, we propose a novel small-molecule inhibitor targeted at the most clinically relevant immune checkpoint, PD-1/PD-L1. The compound is capable of disrupting the PD-1/PD-L1 complex by antagonizing PD-L1 and, therefore, restores activation of T cells similarly to the antibodies, while being cheap in production and possibly nonimmunogenic. The final compound is significantly smaller than others reported in the literature while being nontoxic to cells even at high concentrations. The scaffold was designed using a structure-activity relationship screening cascade based on a new antagonist-induced dissociation NMR assay, called the weak-AIDA-NMR. Weak-AIDA-NMR finds true inhibitors, as opposed to only binders to the target protein, in early steps of lead compound development, and this process makes it less time and cost consuming.
免疫检查点阻断是癌症免疫治疗中最有前途的策略之一。然而，与经典的靶向治疗不同，它目前仅仅基于昂贵的单克隆抗体，这些抗体经常引发免疫相关的不良反应。在此，我们提出了一种针对最具临床相关性的免疫检查点 PD-1/PD-L1 的新型小分子抑制剂。该化合物通过拮抗 PD-L1 来破坏 PD-1/PD-L1 复合物，从而恢复 T 细胞的激活，与抗体的作用类似，但生产成本低廉，并且可能无免疫原性。最终的化合物明显小于文献中报道的其他化合物，即使在高浓度下也对细胞无毒。该支架是使用基于新的拮抗剂诱导的解离 NMR 测定法（称为弱 AIDA-NMR）的结构-活性关系筛选级联设计的。弱 AIDA-NMR 在先导化合物开发的早期步骤中发现真正的抑制剂，而不仅仅是与靶蛋白结合的配体，这一过程使其耗时和成本更低。
