Synthesis and biological evaluation of selective survivin inhibitors derived from the MX-106 hydroxyquinoline scaffold.

Abstract

The survivin (BIRC5) expression is very low in normal differentiated adult tissues, but it is one of the most widely upregulated genes in tumor cells. The overexpression of survivin in many cancer types has been positively correlated with resistance to chemotherapy, tumor metastasis, and poor patient survival. Survivin is considered to be a cancer specific biomarker and serves as a potential cancer drug target. In this report, we describe the design and syntheses of a series of novel selective survivin inhibitors based on the hydroxyquinoline scaffold from our previously reported lead compound MX-106. The best compound identified in this study is compound 12b. Invitro, 12b inhibited cancer cell proliferation with an average IC50 value of 1.4μM, using a panel of melanoma, breast, and ovarian cancer cell lines. The metabolic stability of 12b improved over MX-106 by 1.7-fold (88 vs 51min in human microsomes). Western blot analyses demonstrated that treatments with 12b selectively decreased survivin protein levels, but negligibly affected other closely related members in the IAP family proteins, and strongly induced cancer cell apoptosis. Invivo, compound 12b effectively inhibited melanoma tumor growth when tested using a human A375 melanoma xenograft model. Further evaluation using an aggressive, orthotopic ovarian cancer mouse model showed that 12b was highly efficacious in suppressing both primary tumor growth in ovaries and tumor metastasis to multiple peritoneal organs. Collectively, results in this study strongly suggest that the hydroxyquinoline scaffold, represented by 12b and our earlier lead compound MX-106, has abilities to selectively target survivin and is promising for further preclinical development.