MDM2 Antagonists and p53-Targeting Therapies in Cancer: Clinical Applications, Adverse Effects, and Resistance Mechanisms

Background: Worldwide, cancer is the primary cause of mortality. Research indicates that around half of all cancer types are caused by p53 mutations or downregulation. Alternative or complementary therapy methods are, therefore, desperately needed. The relationship between p53 and the proto-oncoprotein MDM2, a ubiquitin ligase frequently overexpressed in AML that causes the degradation of p53, is an intriguing place to start. Objective: this review aimed to summarize all research on MDM2 inhibitors and clinical studies, and recorded side effects and resistance profile. Methods: Review articles compiled from over 100 publications in PubMed, Scopus, and ClinicalTrials.gov using keywords like MDM2 inhibitors. Results: MDM2 antagonists efficiently stabilize p53, resulting in tumor suppression in malignancies of p53 wild-type individuals. Promising results have been seen in several Phase I and II clinical studies, especially in solid tumors and hematologic malignancies. Adverse effects and medication resistance are still problems, though. P53-targeting medications, on the other hand, may be able to restore P53 function in mutant forms, offering a new treatment option for tumors that have failed previous therapies. Conclusion: P53 medications and MDM2 antagonists mark a substantial breakthrough in targeted cancer therapy. Although the initial clinical outcomes are promising, further investigation is needed to optimize their application, overcome resistance mechanisms, and integrate them into personalized treatment plans. Future developments in understanding P53-MDM2 interactions are likely to lead to more effective cancer treatments.