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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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B7-H1 Antigen / antagonists & inhibitors*
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B7-H1 Antigen / chemistry
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B7-H1 Antigen / metabolism
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Evaluation, Preclinical / methods
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Fatty Acids / chemical synthesis*
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Fatty Acids / metabolism
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Fatty Acids / pharmacology
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Female
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Humans
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Programmed Cell Death 1 Receptor / chemistry
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Programmed Cell Death 1 Receptor / metabolism
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RAW 264.7 Cells
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Rats, Sprague-Dawley
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Treatment Outcome
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Xenograft Model Antitumor Assays / methods
Substances
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Antineoplastic Agents
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B7-H1 Antigen
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Fatty Acids
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Programmed Cell Death 1 Receptor