Design, Synthesis, and Biological Evaluation of Linear Aliphatic Amine-Linked Triaryl Derivatives as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction with Promising Antitumor Effects In Vivo

  • J Med Chem. 2020 Nov 25;63(22):13825-13850. doi: 10.1021/acs.jmedchem.0c01329.
Jialin Guo  1 ,  Longlong Luo  2 ,  Zhihong Wang  2 ,  Naijing Hu  2 ,  Wei Wang  3 ,  Fei Xie  1 ,  Erguang Liang  1 ,  Xinlin Yan  1 ,  Junhai Xiao  1 ,  Song Li  1
Affiliations
  • 1. National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 2. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and ToxicologyBeijing 100850, China.
  • 3. The Affiliated Hospital, Changchun University of Chinese Medicine, Changchun 130021, China.
PMID: 33186040 DOI: 10.1021/acs.jmedchem.0c01329
Abstract

A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 58 could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, 58 restored the T cell function, leading to increased IFN-γ secretion. Moreover, in a humanized mouse model, compound 58 significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that 58 is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for Cancer therapy.

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