A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53

SummaryCancer cells neutralize p53 by deletion, mutation, proteasomal degradation, or sequestration to achieve a pathologic survival advantage. Targeting the E3 ubiquitin ligase HDM2 can lead to a therapeutic surge in p53 levels. However, the efficacy of HDM2 inhibition can be compromised by overexpression of HDMX, an HDM2 homolog that binds and sequesters p53. Here, we report that a stapled p53 helix preferentially targets HDMX, blocks the formation of inhibitory p53-HDMX complexes, induces p53-dependent transcriptional upregulation, and thereby overcomes HDMX-mediated cancer resistance in vitro and in vivo. Importantly, our analysis of p53 interaction dynamics provides a blueprint for reactivating the p53 pathway in cancer by matching HDM2, HDMX, or dual inhibitors to the appropriate cellular context.

Graphical AbstractFigure optionsDownload high-quality image (100 K)Download as PowerPoint slideHighlights
► A stapled p53 helix preferentially targets HDMX with single-digit nanomolar affinity
► SAH-p53-8 blocks the formation of inhibitory p53-HDMX complexes
► HDMX targeting by SAH-p53-8 reactivates the p53 pathway and suppresses tumor growth
► SAH-p53-8 synergizes with Nutlin-3 to overcome p53 antagonism in resistant cancer