Drug Design and Discovery Research Innovation Community, School of Pharmaceutical Sciences, Southern Medical University, Baiyun District, Guangzhou 510515, China.
Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan Wuchang Hospital, Wuchang 430063, China.
J Med Chem. 2020 Dec 24;63(24):15389-15398. doi: 10.1021/acs.jmedchem.0c01362. Epub 2020 Dec 4.
Therapeutic interference of the programmed cell death protein 1(PD-1)/immunosuppressive programmed cell death ligand 1 (PD-L1) signaling pathway by monoclonal antibodies has achieved spectacular success for treating various tumors. However, the development of small molecule inhibitors of PD-1/PD-L1 has lagged far behind due to the challenge of targeting the highly hydrophobic and relatively flat binding interface, despite the benefits small molecule can bring over therapeutic antibodies. This technical challenge provokes the adoption of different strategies in searching for small, medium-sized, and large molecule modulators (e.g., degraders, downregulators, and covalent inhibitors) of the PD-1/PD-L1 protein-protein interaction. In this review article, we discuss latest advances in the development of PD-L1 modulators, with a focus on degraders, downregulators, and covalent inhibitors.
程序性死亡蛋白 1（PD-1）/免疫抑制性程序性死亡配体 1（PD-L1）信号通路的单克隆抗体治疗干预在治疗各种肿瘤方面取得了巨大成功。然而，由于靶向高度疏水且相对平坦的结合界面的挑战，PD-1/PD-L1 的小分子抑制剂的开发远远落后，尽管小分子可以带来治疗抗体的优势。这一技术挑战促使人们采用不同的策略来寻找 PD-1/PD-L1 蛋白-蛋白相互作用的小分子、中分子和大分子调节剂（例如，降解剂、下调剂和共价抑制剂）。在这篇综述文章中，我们讨论了 PD-L1 调节剂的最新进展，重点讨论了降解剂、下调剂和共价抑制剂。
