Abstract
A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppressive activity. A chemical biology approach has succeeded in revealing that 7f is a first inhibitor of epigenetic bromodomain-containing proteins. 7f is expected to become an anti-cancer agent as well as an immunosuppressive agent.
Keywords:
Anti-cancer; BET family; Bromodomain; CD28; Chemical biology; Immunosuppressant; Phenotypic drug discovery.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Azepines / chemical synthesis
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Azepines / chemistry
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Azepines / pharmacology*
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CD28 Antigens / immunology
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CD28 Antigens / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Histone Acetyltransferases
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Histone Chaperones
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Humans
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Immunosuppressive Agents / chemical synthesis
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology*
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Molecular Structure
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism
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Phenotype
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Structure-Activity Relationship
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T-Lymphocytes / cytology*
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
Substances
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Antineoplastic Agents
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Azepines
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CD28 Antigens
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Histone Chaperones
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Immunosuppressive Agents
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Nuclear Proteins
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thienodiazepine substance
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BRD1 protein, human
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Histone Acetyltransferases