Discovery and Optimization of Novel Biphenyl Derivatives Bearing Cyclopropyl Linkage as Potent Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Inhibitors

  • J Med Chem. 2023 May 25;66(10):6811-6835. doi: 10.1021/acs.jmedchem.3c00205.
Tongfei Jing  1 ,  Zhijing Zhang  1 ,  Zhenghui Kang  1 ,  Jianshan Mo  1 ,  Xiaotong Yue  1 ,  Ziyou Lin  1 ,  Xiang Fu  1 ,  Chang Liu  2 ,  Hang Ma  2 ,  Xiaolei Zhang  1 ,  Wenhao Hu  1
Affiliations
  • 1. Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
  • 2. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States.
PMID: 37159395 DOI: 10.1021/acs.jmedchem.3c00205
Abstract

A series of novel compounds bearing a cyclopropyl linkage were designed, synthesized, and evaluated as programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. An optimized compound (1S,2S)-A25 showed potent inhibitory activity against the PD-1/PD-L1 interaction (IC50 = 0.029 μM) with a selected binding affinity with PD-L1 (KD = 1.554 × 10-1 μM). Additionally, under the co-culture with H460/Jurkat cells, (1S,2S)-A25 can reduce the survival of H460 cells in a concentration-dependent way. A liver microsomal assay revealed that (1S,2S)-A25 had favorable metabolic stability. Furthermore, (1S,2S)-A25 displayed favorable pharmacokinetic properties (oral bioavailability of 21.58%) and potent antitumor potency in a LLC1 lung carcinoma model without observable side effects. Data from the flow cytometry and enzyme-linked immunosorbent assays demonstrated that (1S,2S)-A25 suppressed the tumor growth by activating the immune microenvironment. Our study suggests that (1S,2S)-A25 is a promising lead compound for the further development of PD-1/PD-L1 inhibitors.

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