Design,Synthesis And Biological Evaluation Of EGFR/HDAC-based Dual-Target Anticancer Drugs

Cancer has been a frequently-occurring and serious disease which threats to human health.Research shows that over-expression of EGFR receptors and HDACs occur in many solid tumors at the same time.Both of EGFR signaling pathway and HDACs play animportant role in human cancers.EGFR and HDACs have been emerged as attractive targets for the development of antitumor drugs.Increased understanding of the molecular mechanisms that tumors cell proliferation,invasion,motility and metastasis,has led to consensus that the growth and development of cancers are regulated by many receptors and signal pathways.To overcome the low response rate and acquired resistanceto single-target drugs,a number of strategies including combination therapies and multi-targeted RTK inhibitorsto inhibit multiple pathogenic pathways have been tested.A promising approach is the modulation of RTK pathways by the inhibition of histone deacetylases.HD AC inhibitors have been shown to suppress proliferationand induce apoptosis in tumor cells.combined drug therapy frequently induce drug interactions and side effects,but dual-target inhibitors could avoid the adverse reactions cause combined drugs.By incorporating HD AC inhibitory functionality into the pharmacophore of EGFR inhibitors,we synthesized a novel series of compounds with potent,multiacting HDAC and EGFR inhibition.The antiproliferative activities of our compounds were evaluated by MTT method against tumor cell lines A431,H1975 and HeLa,our compound displays potent in vitro antiproliferative activity with same potency of vorinostat(SAHA),Afatinib,CO-1686.Some of them exhibit efficient antiproliferative activity with greater potency than combinations of vorinostat/WZ4002 and vorinostat/CO-1686.The most promising compound LJ-26 also strongly suppressed the proliferation of SW620,HL60,HepG2 and KB cells.Further intensively biological evaluation of the series of compounds is undergoing.