Journal article
Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions
American journal of cancer research, Vol.11(12), pp.5762-5781
01/01/2021
PMCID: PMC8727821
PMID: 35018225
Abstract
Ubiquitination is a key enzymatic post-translational modification that influences p53 stability and function. p53 protein regulates the expression of MDM2 (mouse double-minute 2 protein) E3 ligase and MDMX (double-minute 4 protein), through proteasome-based degradation. Exploration of targeting the ubiquitination pathway offers a potentially promising strategy for precision therapy in a variety of cancers. The p53-MDM2-MDMX pathway provides multiple molecular targets for small molecule screening as potential therapies for wild-type p53. As a result of its effect on molecular carcinogenesis, a personalized therapeutic approach based on the wild-type and mutant p53 protein is desirable. We highlighted the implications of p53 mutations in cancer, p53 ubiquitination mechanistic details, targeting p53-MDM2/MDMX interactions, significant discoveries related to MDM2 inhibitor drug development, MDM2 and MDMX dual target inhibitors, and clinical trials with p53-MDM2/MDMX-targeted drugs. We also investigated potential therapeutic repurposing of selective estrogen receptor modulators (SERMs) in targeting p53-MDM2/MDMX interactions. Molecular docking studies of SERMs were performed utilizing the solved structures of the p53/MDM2/MDMX proteins. These studies identified ormeloxifene as a potential dual inhibitor of p53/MDM2/MDMX interaction, suggesting that repurposing SERMs for dual targeting of p53/MDM2 and p53/MDMX interactions is an attractive strategy for targeting wild-type p53 tumors and warrants further preclinical research.
Details
- Title: Subtitle
- Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions
- Creators
- Murali Munisamy - Department of Translational Medicine Centre, All India Institute of Medical Sciences Department of Pharmacy Practice, Center for Translational Research, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationNayonika Mukherjee - Department of Pharmacy Practice, Center for Translational Research, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationLevin Thomas - Department of Pharmacy Practice, Center for Translational Research, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationAmy Trinh Pham - University of WaterlooArash Shakeri - University of WaterlooYusheng Zhao - University of WaterlooJill Kolesar - University of KentuckyPraveen P N Rao - University of WaterlooVivek M Rangnekar - University of KentuckyMahadev Rao - Manipal Academy of Higher Education
- Resource Type
- Journal article
- Publication Details
- American journal of cancer research, Vol.11(12), pp.5762-5781
- Publisher
- e-Century Publishing Corporation
- PMID
- 35018225
- PMCID
- PMC8727821
- ISSN
- 2156-6976
- eISSN
- 2156-6976
- Language
- English
- Date published
- 01/01/2021
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984696550102771
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