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.
Antineoplastic Agents/pharmacology , Azepines/pharmacology , CD28 Antigens/metabolism , Drug Discovery , Immunosuppressive Agents/pharmacology , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Azepines/chemical synthesis , Azepines/chemistry , CD28 Antigens/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Acetyltransferases , Histone Chaperones , Humans , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Molecular Structure , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/metabolism , Phenotype , Structure-Activity Relationship , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
The next higher homologue of hexamethylenetetramine was synthesized as the proton cryptate H+ @1â Br- (shown schematically), and its X-ray structure determined. The proton trapped by the lone pairs accumulated at the center of the T-symmetric tetraaza cage could not be exchanged or removed, even after heating for three days in 3 M NaOD.
