Design,Synthesis And Biological Evaluation Of Quinoline And Guinoxaline Derivatives As PI3K/mTOR Dual Inhibitors

The PI3K/Akt/mTOR signalling pathway is a key signal transduction system involved in the regulation of cell survival,metabolism,growth and proliferation.Accumulating studies have demonstrated that PI3K/Akt/mTOR signalling is frequently dysregulated in human cancers,resulting in constitutive activation of this signalling network.Therefore,small-molecule inhibitor targeting the key knots PI3K and mTOR in this cellular signalling pathway is considered as the important strategy for cancer therapy.Recently,the research in this field has attracted considerable attention and a sizeable effort has been devoted to development of cancer therapies.Based on the structural features and binding modes of PI3K/mTOR dual inhibitors,using the 6-pyridyl quinoline core presented in GSK2128458,different substituents were introduced into the C-3 and C-4 positions of the quinoline core to generate three series of 70 novel small-molecule inhibitors,including 4-alkynyl.pyridyl quinoline,4-?,?-unsaturated acylamino-6-pyridyl quinoline and 3,4-disubstitUted-6-pyridyl quinoline.Herein,these novel inhibitors were biologically evaluated for their in vitro PI3K? activities,the result of which showed that most of them exhibited better activities than that of the positive control BEZ235.In particular,half of 4-?,?-unsaturated oxo-6-pyridyl quinoline derivatives displayed stronger activities(IC50 = 0.50?0.75 nM)than that of positive control GSK2126458.Additionally,some 4-?,?-unsaturated acylamino-6-pyridyl quinoline derivatives and 3,4-disubstituted-6-pyridyl quinoline derivatives showed activities compared to GSK2126458.In anti-proliferative assays,the tested compounds revealed moderate to potent activity against PC3 and HCT116 cell lines.Among them,10 compounds exhibited better activity(IC50<0.50 ?M)than that of BEZ235 and compared to GSK2126458.It is noteworthy that compounds 1-104 and 1-156 displayed vigorous inhibitory activity against HCT116(IC50 = 0.15 ?M)and PC3(IC50 = 0.08 ?M),respectively,which were more potent than that of BEZ235 and GSK2126458.Besides,the preliminary structure-activity relationships(SARs)of the target compounds were discussed.In the class ? PI3Ks and mTOR enzymatic assays,8 selected compouns displayed strong inhibitory activities,suggesting that those compounds were potent PI3K/mTOR dual inhibitors.The western blot assay indicated that the phosphorylation of pAkt(ser473)can be suppressed by compounds 1-38,1-84,1-87,1-123 and 1-156 at cellular level.Finally,compounds 1-84,1-87,1-123 and 1-156 were selected for pharmacokinetics evaluation.As a result,compound 1-123 was identified the best one with favorable PK properties and was worth further evaluating.Using the quinoxaline core in another PI3K/mTOR dual inhibitor XL-765,target compounds were constructed through the introduction of different substituents into the C-2 and C-3 position of the quinoxaline core.As a result,two series of 64 novel small-molecule inhibitors were synthesized and biologically evaluated for their PI3Ka and mTOR,and none of them exhibited significantly inhibitory activity.However,in anti-proliferative assays,most of them showed better activities than that of the positive control)XL-765.Besides,the SARs of the target compounds were discussed.As for these off-target compounds,some selected compounds were evaluated for a series of tyrosine kinase activities.Unfortunately,no activity was observed in this assay and identification of target is going on.