Discovery of Novel PD-L1 Small-Molecular Inhibitors with Potent In Vivo Anti-tumor Immune Activity

  • J Med Chem. 2024 Mar 11. doi: 10.1021/acs.jmedchem.4c00102.
Liu Liu  1  2 ,  Honghan Zhang  1 ,  Jie Hou  1 ,  Yuying Zhang  1  3 ,  Luosen Wang  1 ,  Shijun Wang  1 ,  Zhiying Yao  1 ,  Tao Xie  1 ,  Xiaoan Wen  1  2 ,  Qinglong Xu  1  2 ,  Liang Dai  1  2 ,  Zhiqi Feng  1  2 ,  Pu Zhang  4 ,  Yaojun Wu  4 ,  Hongbin Sun  1  2 ,  Jun Liu  1  3 ,  Haoliang Yuan  1  2
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
  • 3. New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, China.
  • 4. Jiangsu Flag Chemical Industry Co., Ltd., Nanjing 211500, China.
PMID: 38465588 DOI: 10.1021/acs.jmedchem.4c00102
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: IC50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC50 = 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.

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