Designing novel therapeutics to inhibit oncogenic protein-protein interactions
The Anaphase promoting complex/ cyclosome (APC/C) is a 1.2 MDa multi-subunit E3 ubiquitin ligase that encodes broad substrate-specificity via its two co-activators Cdc20 and Cdh1 and three principal degrons: the D-box, KEN box and ABBA motif. The regulation of mitotic exit is tightly controlled by the expression and degradation of these two co-activators through stages of the cell cycle. The upregulation of Cdc20 is associated with many cancers including pancreatic, breast and cervical cancers and hepatocellular carcinomas. However, to date, no specific inhibitors of the APC/CCdc20 exist in the clinic. Only two APC/C specific compounds have been discovered: TAME/pro-TAME, which disrupts the C-terminal IR tail of Cdc20 binding to APC3, and Apcin, which disrupts substrate D-box degron binding to Cdc20. Recent studies have highlighted the need for a combination strategy to achieve full inhibition of the APC/CCdc20. We propose a new approach involving the design of constrained peptides to inhibit key oncogenic protein-protein interactions with the APC/CCdc20,for the treatment of a wide range of cancers.