Design,Synthesis And Activity Studies Of BET/HDAC Dual-target BI2536 Derivatives

The post-translational modifications(PTMs)of histones plays a key role in regulating gene expression by affecting DNA binding and protein-protein interactions to regulate a series of cellular physiological processes.PTMs can affect differentiation and apoptosis of cells,leading to the occurrence of malignant tumor.As critical proteins of regulation of histone acetylation,Bromodomain(BRD)and histone deacetylase(HDAC)have become important anticancer targets in the field of epigenetics.BRD is a protein domain that specifically recognizes histone acetylated lysine(KAc).BET(Bromodomain and extraterminal domain)are of great value in anti-tumor,anti-infection and anti-viral,and are increasingly concerned by pharmaceutical companies and scientific research institutions.Histone acetylationase(HATs)and histone deacetylase(HDACs)are responsible for regulating the dynamic balance of acetylation and deacetylation of core histones.In cancer,deregulation of HDACs results in upregulation of the transcription of growth-promoting genes,downregulation of tumour suppressor genes as well as the deregulation of microRNA activity.These discoveries led to the development of clinically successful HD AC inhibitors in oncology.Malignant tumors are highly complex and polygenic diseases.Single-targeted drugs cannot kill tumor cells completely,and easily develop resistance.Therefore,it is of great clinical value and scientific significance to study the dual target anti-tumor drugs.This review focuses on the progress of BRD and inhibitors and the progress of HD AC and its inhibitors.We will summarize the structure-activity relationship of different types of BRD and HDAC inhibitors,the discovery and synthesis of BET inhibitor BI-2536 and dual BET/HDAC inhibitors(BI-a,BI-b,BI-c).All compounds were confirmed through 1H NMR,13C NMR and mass spectrometry.Their biologicalactivities on BRD4,HDACs and antitumor activities were evaluated in vitro.Dual-targets inhibitors of BET/HDAC were designed by pharmacophore integration.This study will provides a new strategy for overcoming drug-resistant of tumor by finding candidate compounds with dual-targets action.