Investigation Of Novel P53/PDK1 And ErbB/HDAC Multitarget Compounds For Cancer Therapy

Because of the heterogeneities and complexities of tumor cells,systems biology-based multitarget drugs may possess better advantages than selective mono-target drugs.p53,PDK1,EGFR,HER2,and HDAC are associated with a variety of cellular processes,such as cell cycle arrest,differentiation,apoptosis,and survival.Many studies have shown that there is synergistic crosstalk between p53/MDM2/PDK1or EGFR/HER2/HDAC.Simultaneous and synergistic inhibitions on p53/MDM2/PDK1or EGFR/HER2/HDAC pathways might have the great potential to improve the response rates or overcome the resistance in cancer therapy.The first part of the thesis is design,synthesis and anticancer research of dual-target inhibitors of MDM2 and PDK1.We design and identify 5 series of potent small-molecule inhibitor of MDM2-p53 interaction,which can reactivate wild-type p53for the tumor suppressor function.Further mechanistic study on compound A3 revealed that A3 caused p53 accumulation as a result of the increased half-life of p53.Treatment of A3 blocked p53–HDM-2 binding in vitro and increased the expression of MDM2 and p21.A3 could induce p53-dependent G0/G1 cell cycle arrest and intrinsic apoptosis.A3also inhibited the PDK1 kinase thus blocking AKT pathway in a p53-independent manner.Simultaneously targeting these two targets could play a concerted role in inducing cell cycle arrest,intrinsic apoptosis and substantial antitumor effect in vivo.The second part of the thesis is design,synthesis and anticancer research of multitarget inhibitors of EGFR,HER2,and HDAC.In this study,by merging the critical pharmacophores of Erb B and HDAC inhibitors into one compound,two novel series of EGFR,HER2,and HDAC multitarget inhibitors were synthesized.Compounds F1-F4and G1-G18,which contained 4-anilinoquinazolines with triazole-linked long alkyl chains of hydroxamic acid,displayed excellent inhibitory activities against these enzymes(compound G6 exhibited the best inhibitory potencies on wild-type EGFR,HDAC1,and HDAC6 with IC₅₀ values 0.12 nM,0.72 nM and 3.2 nM individually)and made great changes in selectivity profiles between kinases.Furthermore,compounds G2,G6,G16 and G18 potently inhibited proliferation of five human cancer cell lines(with IC₅₀ values between 0.26-16.55μM).Further mechanistic study revealed that compound G6 regulated the phosphorylation of EGFR and HER2 and histone H3hyperacetylation on the cellular level and induced remarkable G1 and G2/M cell cycle arrest in A549 and BT-474 cells respectively.G6 also induced apoptosis in BT-474cells obviously.These system network-based EGFR,HER2,and HDAC multitarget inhibitors may offer better benefits than single-targeted inhibitors in cancer therapy.