In this report, the design and syntheses of a series of dual MDM2/XIAP inhibitors based on the tetrahydroquinoline scaffolds I [R = 3-EtC6H4, 3-C(O)MeC6H4, 3,4-(Me)2C6H3, etc.; R1 = cyclohexyl, Ph, 4-C(O)CH(Me)2C6H4, etc.] and II [R2 = 3,4-(Me)2C6H3, 3-C(O)MeC6H4] from previously reported lead compound JW-2-107 and tested their cytotoxicity in a panel of human cancer cell lines was described.The best compound identified in this study was compound I [R = 3-C(O)MeC6H4; R1 = 4-C(O)CH(Me)2C6H4].Western blot analyses demonstrated that treatments with compounds I [R = 3-C(O)MeC6H4; R1 = 4-C(O)CH(Me)2C6H4] decreased MDM2 and XIAP protein levels and increased expression of p53, resulted in cancer cell growth inhibition and cell death.Furthermore, compound I [R = 3-C(O)MeC6H4; R1 = 4-C(O)CH(Me)2C6H4] effectively inhibited tumor growth in vivo when tested using a human 22Rv1 prostate cancer xenograft model.Collectively, results in this study strongly suggested that the tetrahydroquinoline scaffold, represented by compound I [R = 3-C(O)MeC6H4; R1 = 4-C(O)CH(Me)2C6H4] and earlier lead compound JW-2-107, had abilities to dual target MDM2 and XIAP and was promising for further preclin. development.