Drug Discovery And Mechanism Studies Targeting PRMT5 And BRD4 Proteins

Epigenetics refers to a reversible and heritable phenomenon for attributing to change gene expression pattern,however influences in the underlying DNA sequence of the gene are not involved.Its process includes DNA methylation,non-coding RNA regulation,and histone modification,etc.Over the past decades,major progress in the field of epigenetics had been made,and the numerous studies of epigenetic pathways showed that epigenetics has very important significance in diverse biological processes.Genome-wide changes in gene expression can lead to serious disease consequences such as hematologic malignancies,solid tumors and immune.By exploringthe mechanism of epigenetic and disease,it is helpful to discover the drug and disease treatment.Protein arginine methyltransferase 5(PRMT5)plays some important roles in diverse cellular process,and is documented upregulated in several human malignancies.In addition,PRMT5 isvalidated as anti-cancer target in mantle cell lymphoma(MCL).In this study,we found a potent and selective PRMT5 inhibitor by combination of structure-based virtual screening and pharmaceutical chemistry synthesis modification.The identified small molecuμe 17 exhibited a half-maximal inhibitory concentration(IC50)of 0.33 μM and broad selectivity against a panel of other methyltransferases.Treatment of leukemia and lymphoma cells with 17 showed selective anti-proliferative effects in MV4-11 cells,and further studies indicated that the cellular antitumor activity mechanism is resulted from inhibition of PRMT5 substrate SmD3 methylation.17 may represent a promising lead compound to understand more about the molecular target of PRMT5 and potentially assist the development of leukemia indications.Bromodomain is a protein domain that can be specifically identified with acetylated histones.BRD4 is a recognition factor that recognizes histone acetylation and is part of the BET protein family.BRD4 has been confirmed as a therapeutic target,including MLL,AML,MM,ALL,and breast cancer,midline cell carcinoma,etc.BRD4 plays a key role in maintaining the level of histone acetylation,which can also regulate oncogenes and anti-apoptotic proteinsand ultimately cause stable inhibition of cancer development.The discovery of small molecule inhibitors such as JQ1,IBET151 and IBET762 has promoted the study of targeting BET family.Here,we performed cellular assays to discovery anti-proliferative mechanism of the small molecular compound.Compound DCBD008 showed strong anti-proliferative activity in THP-1 cells,with EC50= 8.098 μM.DCBD008 had been confirmed to block G0/G1 phase and induced THP-1 cells apoptosis.The expression of CDK6,BCL2 and C-MYC genes in THP-1 cells decreased in a concentration-dependent way,indicating that DCBD008 can target to inhibit BRD4 to play an anti-cancer effect.Summary,this study provided a promising chemical scaffold for the development of chemical probes and drug candidates against BRD4.