ABSTRACT
Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1â¯at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
Subject(s)
Azepines/chemistry , Drug Discovery , Proteins/antagonists & inhibitors , Pyrazoles/chemistry , Animals , Azepines/chemical synthesis , Azepines/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Domains , Proteins/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
BACKGROUND: Psychotropic drug changes during medical hospitalizations may lead to psychiatric and medical readmissions. METHODS: One-year hospitalization records of nursing home patients with chronic mental illness and a psychotropic drug change during medical admission were reviewed. We calculated the readmission rates for 30, 60, and 90 days; the classes of the psychotropic drugs changed; the reason for change; and the specialties of the responsible physicians. The readmission rates were compared with those of an age-matched control group. RESULTS: The changes were associated with an increase in psychiatric readmission rates of 2.7% (30 days), 5.4% (60 days), and 14.9% (90 days). The 90 days readmission rate reached statistical significance (14.9% vs 2.7%; OR = 6.29; P = .020). The family practice team was responsible for the highest psychiatric readmission rate (18.4%). The most significant reasons for change included human errors (up to 40%), which is alarming. CONCLUSIONS: Judicious changes, attempts at re-titration, and appropriate documentation of reasons for change on discharge records may reduce the readmission rates.
