Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein–Protein Interaction

We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors.本研究报道了一类基于三联苯母核的强效PD-L1/PD-1抑制剂，该母核衍生自以联苯结构为灵感并经刚性化修饰的骨架。我们通过计算机虚拟分子对接技术设计了该类三联苯骨架抑制剂，并借助多种生物物理与生物化学实验手段，验证了其阻断PD-1/PD-L1复合物形成的有效性。此外，我们解析了PD-L1与本研究中一款强效抑制剂的复合物高分辨率结构，从而在分子层面阐明了PD-L1与抑制剂之间的关键相互作用。除此之外，我们利用健康供体来源的原代人免疫细胞，证实了本研究中强效抑制剂激活抗肿瘤免疫应答的功效。