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

• Published in: Chemical biology & drug design 2023-07, Vol.102 (1), p.126-136
• Main Authors: Mukherjee, Srijata, Saha, Gouranga, Roy, Neeladri Sekhar, Naiya, Gitashri, Ghosh, Mrinal K., Roy, Siddhartha
• Format: Article
• Language: English
• Subjects: HDM2; inhibition; p53; peptide; Peptides - metabolism; Peptides - pharmacology; Proto-Oncogene Proteins c-mdm2; synergy; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin-Specific Peptidase 7 - metabolism; USP7
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.14255

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. Synergistic combinations of inhibitors are sought after. A small helically‐constrained peptide potently inhibited p53‐HDM2 interaction and exerted anti‐proliferative effects on p53+/+ cells. A combination of this peptide and a USP7 inhibitor showed synergistic anti‐proliferative effects. Synergistic inhibition of two important drug targets may lead to novel therapeutic strategies.