Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation

Abstract

Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its “undruggable” nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization. One of the scaffolds, represented by the compound LQZ-7, contains an undesirable labile hydrazone linker and a potentially nonfunctional furazanopyrazine ring that we attempted to eliminate in this study. We found one compound, 7I, that is more active than the parent compound, LQZ-7, and when given orally effectively inhibits xenograft tumor growth and induces survivin loss in tumors. These findings indicate that 7I with a stable linker and a quinoxaline ring can be used as a lead for further optimization of this novel class of survivin inhibitors.