ABSTRACT
Dysfunction of the bromo and extra terminal domain (BET) family proteins is associated with many human diseases, therefore the BET family proteins have been considered as promising targets for drug development. Numerous small molecular compounds targeting the N-terminal two tandem bromodomains BD1 and BD2 of the BET family proteins have been reported, and a number of them have been advanced into clinical trials. Most of the BET inhibitors entered clinical trials are pan-BET inhibitors which show poor selectivity among BET members and bind to the BD1 and BD2 of the BET family proteins with comparable binding affinities. In order to elucidate the distinct functions of BD1s and BD2s, many BD1 and BD2 selective BET inhibitors have also been developed. In this review, we summarized the recent progress in the development of BD1 and BD2 selective BET inhibitors, and provided the perspectives for future studies of BET inhibitors.
Subject(s)
Azepines/pharmacology , Drug Development , Proteins/antagonists & inhibitors , Triazoles/pharmacology , Azepines/chemical synthesis , Azepines/chemistry , Humans , Molecular Structure , Protein Domains/drug effects , Proteins/chemistry , Proteins/metabolism , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Soy isoflavones exhibit various biological activities, such as antioxidant, anti-tumor, anti-inflammatory, and cardiovascular protective effects. The present study was designed to investigate the effects of sixteen synthesized 3-amino-2-hydroxypropoxy genistein derivatives on cell proliferation and activation of Nrf2 (Nuclear factor erythroid 2-related factor 2)/ARE (antioxidant response elements) pathway in human cancer cell lines. Most of the tested compounds exerted greater cytotoxic activity than genistein, as measured by MTT assay. Moreover, compound 8c showed the highest ARE-luciferase reporter activity among the test compounds. It strongly promoted Nrf2 nuclear translocation and up-regulated the expression of total Nrf2 and downstream targets NQO-1 and HO-1 at protein level. The present study may provide a basis for the application of isoflavone derivatives as Nrf2/ARE pathway inducers for cancer therapy and cancer prevention.
