156 Behaviour of platinum(IV) complexes with prodrug function in different models of hypoxia

Abstract

utility. Recently, inhibitors of spindle-regulatory proteins have attracted considerable attention, and transforming acidic coiled-coil-3 (TACC3) is a spindle-regulatory protein overexpressed in many human cancers. We have developed a protein knockdown system to induce degradation of target proteins via the ubiquitin–proteasome system in cells with hybrid molecules named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser). In this study, we designed and synthesized novel SNIPER(TACC3)s that target TACC3 for degradation, and evaluated their activity in vitro. SNIPER(TACC3)s induce poly-ubiquitylation and proteasomal degradation of TACC3, and reduce the TACC3 protein level in cells. Mechanistic analysis indicated that the ubiquitin ligase APC/C mediates the SNIPER(TACC3)-induced degradation of TACC3. Cancer cells express larger amount of TACC3 than do normal fibroblasts, and SNIPER(TACC3) selectively induced cell death in cancer cells. These results suggest protein knockdown of TACC3 by SNIPER(TACC3) is a potential strategy to treat cancers overexpressing the TACC3 protein.