Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy

  • J Med Chem. 2024 May 23;67(10):7995-8019. doi: 10.1021/acs.jmedchem.4c00128.
Zichao Yang  1 ,  Ziqing Liu  1 ,  Shanhe Wan  1 ,  Jianwei Xu  1 ,  Yaqi Huang  1 ,  Haiqi He  1 ,  Ting Liu  1 ,  Ling Li  2 ,  Yichang Ren  1 ,  Jiajie Zhang  1 ,  Jianjun Chen  1
Affiliations
  • 1. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2. The Eighth Affiliated Hospital, Sun Yat sen University, Shenzhen 518033, China.
PMID: 38739112 DOI: 10.1021/acs.jmedchem.4c00128
Abstract

Based on the close relationship between programmed death protein ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) in glioblastoma (GBM), we designed and synthesized a series of small molecules as potential dual inhibitors of EGFR and PD-L1. Among them, compound EP26 exhibited the highest inhibitory activity against EGFR (IC50 = 37.5 nM) and PD-1/PD-L1 interaction (IC50 = 1.77 μM). In addition, EP26 displayed superior in vitro antiproliferative activities and in vitro immunomodulatory effects by promoting U87MG cell death in a U87MG/Jurkat cell coculture model. Furthermore, EP26 possessed favorable pharmacokinetic properties (F = 22%) and inhibited tumor growth (TGI = 92.0%) in a GBM mouse model more effectively than Gefitinib (77.2%) and NP19 (82.8%). Moreover, EP26 increased CD4+ cells and CD8+ cells in tumor microenvironment. Collectively, these results suggest that EP26 represents the first small-molecule-based PD-L1/EGFR dual inhibitor deserving further investigation as an immunomodulating agent for Cancer treatment.

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