Design,Synthesis And Biological Activities Of Smo/Bcr-Abl Dual-target Nilotinib Derivatives

Chronic myelogenous leukemia?CML?is a malignant blood systemic tumor.The first generation of Bcr-Abl tyrosine kinase inhibitor?TKI?-imatinib targeting the pathogenesis of CML has brought new vitality to patients.Although the recovery rate of TKI therapy are impressive,its resistance remains a clinical challenge.Drug-resistant mutations destroy the effective binding of inhibitors to kinases,leading the result that patients lose their initial response to the drug quickly and then relapse.As the widespread study of Hedgehog signal pathway in blood malignant tumor,an increasing evidence shows that the Hedgehog signal pathway is closely associated with the occurrence and development of CML.In stem cells and grandmother cells of Bcr-Abl positive,Hedgehog signaling pathway is activated.The ligand protein Smo of Hedgehog signaling pathway can be used as a drug target to inhibit CML stem cells.Since Bcr-Abl and Smo proteins are correlated with hematologic malignancies,a series of double-targeted Smo/Bcr-Abl inhibitors were designed.Multi-target drugs expected to overcome the drug resistance of single-target drugs have fewer side effects and better efficacy than combination drugs.Nilotinib was a TKI.However,according to previous research,it also displayed some activity on Smo.Thus,it was chosen as the lead compound.Based on the structures of Nilotinib and Smo inhibitors reported,eight double target compounds were designed and synthesized.The Bcr-Abl kinase,Hh signaling pathway and Smo protein inhibitory activities of the compounds were assessed.Among them,compound A3 and C2 displayed potent inhibitory activity for Abl kinase,especially compound A3 with IC₅₀ value of 0.112?M.Besides,A3exhibited potent activities for Hh signal pathway and Smo protein with IC₅₀ value of 0.27,0.41?M,respectively.