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.
Subject(s)
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/metabolismABSTRACT
A new class of Aurora A kinase inhibitor was created by transforming 4-(5-methyl-3-pyrazoloamino)pyrimidine moiety of VX-680 to 3-cyano-6-(5-methyl-3pyrazoloamino)pyridine. Compound 6 exhibited a potent Aurora A kinase inhibitory activity, excellent selectivity to Aurora B kinase and other 60 kinases, good cell permeability and good PK profile. Therefore compound 6 was effective in antitumor mice model at a dose of 30 mg/kg po qd without decrease of body weight.
