2. Academic Validation
  3. Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage

Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage

  • J Med Chem. 2021 Nov 25;64(22):16687-16702. doi: 10.1021/acs.jmedchem.1c01422.
Zilan Song 1 2 3 4,  Bo Liu 2,  Xia Peng 3,  Wangting Gu 1,  Yiming Sun 2,  Li Xing 1,  Yi Xu 5,  Meiyu Geng 2 3 4,  Jing Ai 2 4,  Ao Zhang 1 2 3 4 6
Affiliations

Affiliations

  • 1 Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Shanghai Pinghe School, 261 Huangyang Road, Shanghai 201206, China.
  • 6 School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
PMID: 34761679 DOI: 10.1021/acs.jmedchem.1c01422
Abstract

Blockade of immune checkpoint PD-1/PD-L1 has been a promising Anticancer strategy; however, clinically available PD-1/PD-L1 small-molecule inhibitors are lacking. In view of the high potency of compound 2 (BMS-1002), structural fine tuning of the methoxy linkage together with diverse modification in the solvent interaction region was conducted. A series of novel derivatives featuring a difluoromethyleneoxy linkage were designed. Compound 43 was identified as the most promising PD-1/PD-L1 inhibitor with an IC50 value of 10.2 nM in the HTRF assay. This compound is capable of promoting CD8+ T cell activation through inhibiting PD-1/PD-L1 cellular signaling. Moreover, in the Hepa1-6 syngeneic mouse model, administration of compound 43 at 1 mg/kg dosage promoted CD8+ T cell activation and delayed the tumor growth with good tolerance. Notably, the tumor in one mouse of the compound 43-treated group was completely regressed. These results indicate that compound 43 is a promising candidate worthy of further investigation.

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