A phenotypic drug discovery study on thienodiazepine derivatives as inhibitors of T cell proliferation induced by CD28 co-stimulation leads to the discovery of a first bromodomain inhibitor

Bioorg Med Chem Lett. 2016 Mar 1;26(5):1365-70. doi: 10.1016/j.bmcl.2016.01.084. Epub 2016 Feb 2.

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.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Histone Chaperones
  • Humans
  • Immunosuppressive Agents / chemical synthesis
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / pharmacology*
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Phenotype
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Antineoplastic Agents
  • Azepines
  • CD28 Antigens
  • Histone Chaperones
  • Immunosuppressive Agents
  • Nuclear Proteins
  • thienodiazepine substance
  • BRD1 protein, human