# The Structure, Pathogenesis, and Inhibition of the p53-MDM2 Pathway

## TL;DR

This review discusses the p53-MDM2 pathway's role in cancer and explores new non-covalent inhibitors as potential anti-cancer therapies.

## Contribution

The paper highlights non-covalent MDM2 inhibitors as a novel therapeutic strategy for cancers with wild-type or mutant p53.

## Key findings

- Non-covalent MDM2 inhibitors like AQ-101 show promising anti-cancer activity with reduced toxicity.
- MDM2 overexpression or amplification can drive tumorigenesis even in cancers with wild-type p53.
- Structural features of MDM2, such as its RING domain, are key targets for therapeutic development.

## Abstract

Dysregulation of the p53 tumor suppressor protein has been shown to be a common mechanism underlying the pathogenesis of various types of cancers. A major protein involved in p53 disruption and degradation is the negative regulator MDM2. Several compounds targeting the p53-MDM2 pathway have been developed as promising anti-cancer therapies. Most of these strategies have acted against the p53-MDM2 binding interaction; however, recent research has turned toward inhibiting the MDM2 RING domain. In this review, we outline the structural features of the MDM2 protein, summarize its role in cancer pathogenesis, and review current and promising therapeutic strategies for targeting the p53-MDM2 pathway.

The p53 tumor suppressor protein plays a central role in maintaining genomic stability by regulating cell cycle arrest, apoptosis, and DNA repair under cellular stress. Mouse double minute 2 (MDM2), an E3 ubiquitin ligase, negatively regulates p53 via direct binding and proteasomal degradation. Overexpression or amplification of MDM2 can disrupt this pathway and promote tumorigenesis, even in cancers with wild-type p53. This review outlines the structural features of MDM2, particularly its N-terminal hydrophobic pocket and C-terminal RING domain, and their roles in p53 regulation. We further examine the pathological effects of MDM2 dysregulation and SNPs linked to increased cancer risk. Recent progress in small molecule MDM2 inhibitors is discussed, with a focus on non-covalent agents such as rhein-derived anthraquinone analogs, including AQ-101, which demonstrate promising anti-cancer activity with reduced toxicity. These findings support the continued development of non-covalent MDM2 inhibitors as a novel therapeutic approach for cancers involving both wild-type and mutant p53.