2. Academic Validation
  3. Design, Synthesis, and Antitumor Activity Evaluation of 2-Arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) Benzylamine Derivatives as Potent PD-1/PD-L1 Inhibitors

Design, Synthesis, and Antitumor Activity Evaluation of 2-Arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) Benzylamine Derivatives as Potent PD-1/PD-L1 Inhibitors

  • J Med Chem. 2023 Aug 10;66(15):10579-10603. doi: 10.1021/acs.jmedchem.3c00731.
Hua Zhang 1 2,  Shijia Zhou 1 2,  Jacek Plewka 3,  Caiyun Wu 1 2,  Mengyu Zhu 1 2,  Qimeng Yu 1 2,  Bogdan Musielak 3,  Xiao Wang 1 2,  Annoor Awadasseid 1 2,  Katarzyna Magiera-Mularz 3,  Yanling Wu 4,  Wen Zhang 1 2
Affiliations

Affiliations

  • 1 Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
  • 2 Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China.
  • 3 Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.
  • 4 Lab of Molecular Immunology, Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China.
PMID: 37496104 DOI: 10.1021/acs.jmedchem.3c00731
Abstract

Novel 2-arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) benzylamine derivatives were designed, synthesized, and evaluated in vitro and in vivo against cancers as PD-1/PD-L1 inhibitors. Through the computer-aided structural optimization and the homogeneous time-resolved fluorescence (HTRF) assay, compound A56 was found to most strongly block the PD-1/PD-L1 interaction with an IC50 value of 2.4 ± 0.8 nM and showed the most potent activity. 1H NMR titration results indicated that A56 can tightly bind to the PD-L1 protein with KD < 1 μM. The X-ray diffraction data for the cocrystal structure of the A56/PD-L1 complex (3.5 Å) deciphered a novel binding mode in detail, which can account for its most potent inhibitory activity. Cell-based assays further demonstrated the strong ability of A56 as an hPD-1/hPD-L1 blocker. Especially in an hPD-L1 MC38 humanized mouse model, A56 significantly inhibited tumor growth without obvious toxicity, with a TGI rate of 55.20% (50 mg/kg, i.g.). In conclusion, A56 is a promising clinical candidate worthy of further development.

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