Discovery and Crystallography Study of Novel Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

  • J Med Chem. 2025 Jun 26;68(12):12593-12614. doi: 10.1021/acs.jmedchem.5c00344.
Zichao Yang  1 ,  Pan Yang  2  3 ,  Jianwei Xu  1 ,  Xixiang Yang  1 ,  Jiayi Zhou  1 ,  Haiqi He  1 ,  Ling Li  4 ,  Yichang Ren  1 ,  Meirong Chen  2  3 ,  Yibei Xiao  2  3 ,  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. State Key Laboratory of Natural Medicines and Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3. Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
  • 4. The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China.
PMID: 40518797 DOI: 10.1021/acs.jmedchem.5c00344
Abstract

Current studies on PD-1/PD-L1 small-molecule inhibitors mainly focus on modifying the linker region between the biphenyl ring and amino acid side chains, or transforming the biphenyl ring into a benzodioxane structure. Herein, we designed and synthesized a series of compounds by introducing a tail at the terminal phenyl ring as small-molecule PD-1/PD-L1 inhibitors. Among them, compound NPH16 exhibited the most potent PD-L1 inhibitory activity (IC50 = 24.4 nM). The X-ray crystal structure further confirmed the high binding affinity of NPH16 to PD-L1 dimer. In the HepG2/Jurkat T cell coculture model, NPH16 promoted HepG2 cell Apoptosis dose-dependently. In addition, NPH16 showed excellent in vivo antitumor efficacy (TGI = 92.1%) in a Hepa1-6 mouse tumor model and increased CD8+ cells in tumor microenvironment. Importantly, NPH16 possessed favorable pharmacokinetic properties with an oral bioavailability of 15.9%. Collectively, compound NPH16 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential Anticancer agent.

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