Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy

  • J Med Chem. 2024 Feb 13. doi: 10.1021/acs.jmedchem.3c02362.
Yongling Xu  1 ,  Huijie Du  1 ,  Weibo Guo  1  2 ,  Beibei Liu  1 ,  Wenxin Yan  1 ,  Chi Zhang  2 ,  Long Qin  2 ,  Jingling Huang  1 ,  Hongxia Wang  1 ,  Shiqi Wu  1 ,  Weijie Ren  1 ,  Yi Zou  1 ,  Jie Wang  3 ,  Qihua Zhu  1 ,  Yungen Xu  1 ,  Hongfeng Gu  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Xi'an Xintong Pharmaceutical Research Co., Ltd, Xi'an 710061, China.
  • 3. China Pharmaceutical University Center for Analysis and Testing, China Pharmaceutical University, Nanjing 211198, China.
PMID: 38348878 DOI: 10.1021/acs.jmedchem.3c02362
Abstract

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in Cancer Immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast Cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.

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