Design,Synthesis And Biological Activity Study Of BRD4 Inhibitors

Post-translational modification of histones(PTM)is an important component of epigenetic regulation.Among them,the acetylation of histone lysine is an important mechanism for regulating chromatin structure and activation of transcription.Currently,one of the most widely studied PTM is acetylation.It is regulated by a variety of family of enzymes and proteins together,the whole process through the three categories of regulatory proteins,"writers","erasers",and "readers" to accomplish physiological role of gene transcription.Key to this process is the ability of "readers"-bromodomain(BRD)to recognize specific PTMs that ultimately determine the functional outcome.Acetylation level anomalies often associated with the occurrence of many diseases,such as malignant tumors,inflammation,autoimmune diseases,metabolic diseases.Therefore,targeting these proteins for the development of targeted cancer,inflammation and viral infections of new therapeutic strategies may be beneficial.Recently,a number of small-molecule bromodomain and extra terminal domain(BET)inhibitors with potent inhibitory have been reported.According to the structural characteristics of inhibitors,it can be divided into diazepine;3,5-dimethyl-isoxazole and quinazolone template.In this paper,the protein BRD4 as a target,based on the binding mode of small molecule compounds 3-methyl-2H-quinazolone and BRD4 protein,we retain the amide moiety which interact with asparaginate(Asn)140,designing 2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one as our lead compound,further structural optimization gains 44 new compounds which is the innovations of the article,including 21 oxazine compounds substituted by sulfonyl-amino,18 oxazine compounds substituted by amino-sulfonyl,5 pyridine and six-membered heterocycle compounds.The data demonstrated that small molecule inhibitors of oxazine compounds substituted by amino-sulfonyl 30-43 exhibited good biological activities,with IC50 values between 1 and 12 μM generally.Compounds 38,39,40 and 41 are the most potent binding to the BRD4.IC50 values are 2.73,1.44,1.99 and 2.96μM respectively.At the same time,the co-crystal structure of compound 40 in complex with BRD4 protein is obtained and this is another innovation of this paper.Our work may provide reference for efficient and selective inhibitor synthesis of BRD4 in the future.