A small HDM2 antagonist peptide and a USP7 inhibitor synergistically inhibit the p53‐HDM2‐USP7 circuit

Abstract

HDM2, an E3 ubiquitin ligase, is a crucial regulator of many proliferation‐related pathways. It is also one of the primary regulators of p53. USP7, a deubiquitinase, also plays a key role in the regulation of both p53 and HDM2, thus forming a small regulatory network with them. This network has emerged as an important drug target. Development of a synergistic combination targeting both proteins is desirable and important for regulating this module. We have developed a small helically constrained peptide that potently inhibited p53‐HDM2 interaction and exerted anti‐proliferative effects on p53+/+ cells. A combination of this peptide—when attached to cell entry and nuclear localization tags—and a USP7 inhibitor showed synergistic anti‐proliferative effects against cells harboring wild‐type alleles of p53. Synergistic inhibition of two important drug targets may lead to novel therapeutic strategies.