Discovery of Novel PD-L1 Small-Molecular Inhibitors with Potent <i>In Vivo</i> Anti-tumor Immune Activity
Liu Liu, Honghan Zhang, Jie Hou, Yuying Zhang, Luosen Wang, Shijun Wang, Zhiying Yao, Tao Xie, Xiaoan Wen, Qing‐Long Xu, Liang Dai, Zhiqi Feng, Pu Zhang, Yaojun Wu, Hongbin Sun, Jun Liu, Haoliang Yuan
Abstract
Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction ( X18: IC 50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells ( X18: EC 50 = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8 + T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.