a Department of Drug Design , University of Groningen , Groningen , The Netherlands.
b Faculty of Chemistry , Jagiellonian University , Cracow , Poland.
Expert Opin Ther Pat. 2018 Sep;28(9):665-678. doi: 10.1080/13543776.2018.1512706. Epub 2018 Sep 10.
The protein-protein interaction PD1/PD-L1 is an important immune checkpoint and several recently approved monoclonal antibodies show promising anti cancer activities in the clinical practice. However, only a small percentage of cancer patients benefit from PD1/PD-L1 directed mAbs. Moreover, some patients experience immune related side effects upon treatment with these mAbs. Recently, several atomic-resolution structures of human PD1/PD-L1, and small molecules, peptides and mAbs with PD-L1 and PD1 open the field for structure based drug design. Small molecules and peptides targeting PD1/PD-L1 promise to enhance tumor activity while showing less immune related side effects.
We reviewed the small molecules classes and peptides targeting PD1/PD-L1.
Currently approved PD1/PD-L1 directed therapeutics show room for improvement. Three classes of non mAb small molecule classes have been discovered so far: (cyclic) peptides as direct competitive PD1/PD-L1 antagonists; small molecules disrupting PD1/PD-L1 and inducing a PD-L1 dimerization; and a small molecule class of unknown mode-of-action. An example of the later group CA-170 is currently investigated in a Phase 1 trial in patients with advanced solid tumors and lymphomas. Potential advantages of small molecules over mAbs include high distribution and better tumor penetration, improved PK/PD, less side effects and oral bioavailability.
蛋白-蛋白相互作用 PD1/PD-L1 是一个重要的免疫检查点，最近批准的几种单克隆抗体在临床实践中显示出有前景的抗癌活性。然而，只有一小部分癌症患者能从 PD1/PD-L1 定向 mAb 中获益。此外，一些患者在接受这些 mAb 治疗时会出现免疫相关的副作用。最近，人类 PD1/PD-L1 的几个原子分辨率结构，以及与 PD-L1 和 PD1 结合的小分子、肽和 mAb，为基于结构的药物设计开辟了道路。针对 PD1/PD-L1 的小分子和肽有望增强肿瘤活性，同时显示出较少的免疫相关副作用。
我们综述了针对 PD1/PD-L1 的小分子和肽类。
目前批准的 PD1/PD-L1 定向治疗药物还有改进的空间。迄今为止，已经发现了三类非 mAb 小分子类：（环状）肽作为直接竞争性 PD1/PD-L1 拮抗剂；小分子破坏 PD1/PD-L1 并诱导 PD-L1 二聚化；以及一类作用机制未知的小分子类。后者 CA-170 目前正在晚期实体瘤和淋巴瘤患者的 1 期试验中进行研究。小分子相对于 mAb 的潜在优势包括高分布和更好的肿瘤穿透性、改善 PK/PD、较少的副作用和口服生物利用度。
