Recent advances on the intervention sites targeting USP7-MDM2-p53 in cancer therapy

Chrisanta Harakandi; Lauraine Nininahazwe; Haiwei Xu; Bingrui Liu; Chenghua He; Yi-Chao Zheng; Hang Zhang

doi:10.1016/j.bioorg.2021.105273

Recent advances on the intervention sites targeting USP7-MDM2-p53 in cancer therapy

Bioorg Chem. 2021 Nov:116:105273. doi: 10.1016/j.bioorg.2021.105273. Epub 2021 Aug 21.

Authors

Chrisanta Harakandi¹, Lauraine Nininahazwe¹, Haiwei Xu¹, Bingrui Liu², Chenghua He³, Yi-Chao Zheng¹, Hang Zhang⁴

Affiliations

¹ Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
² College of Public Health, North China University of Science and Technology, Tangshan 063503, China.
³ College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
⁴ Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. Electronic address: hangzhang@zzu.edu.cn.

PMID: 34474304
DOI: 10.1016/j.bioorg.2021.105273

Abstract

The ubiquitin-specific protease 7 (USP7)-murine double minute 2 (MDM2)-p53 network plays an important role in the regulation of p53, a tumor suppressor which plays critical roles in regulating cell growth, proliferation, cell cycle progression, apoptosis and immune response. The overexpression of USP7 and MDM2 in human cancers contributes to cancer initiation and progression, and their inhibition reactivates p53 signalings and causes cell cycle arrest and apoptosis. Herein, the current state of pharmacological characterization, potential applications in cancer treatment and mechanism of action of small molecules used to target and inhibit MDM2 and USP7 proteins are highlighted, along with the outcomes in clinical and preclinical settings. Moreover, challenges and advantages of these strategies, as well as perspectives in USP7-MDM2-p53 field are analyzed in detail. The investigation and application of MDM2 and USP7 inhibitors will deepen our understanding of the function of USP7-MDM2-p53 network, and feed in the development of effective and safe cancer therapies where USP7-MDM2-p53 network is implicated.

Keywords: Cancer therapy; MDM2 and USP7 inhibition; USP7-MDM2-p53 network; p53 activiation.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Humans
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / metabolism
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Tumor Suppressor Protein p53 / antagonists & inhibitors*
Tumor Suppressor Protein p53 / metabolism
Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors*
Ubiquitin-Specific Peptidase 7 / metabolism

Substances

Antineoplastic Agents
Small Molecule Libraries
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
USP7 protein, human
Ubiquitin-Specific Peptidase 7