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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Structural and Drug Targeting Insights on Mutant p53
Ana Sara Gomes1, Helena Ramos1, Alberto Inga2
1LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
Abstract:
p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53.
Insights
Mutant p53 (mutp53) drives cancer, but compounds can restore its normal function. Structural insights are key to developing new p53-targeted cancer therapies.
Area of Science:
- Molecular Biology
- Biochemistry
- Oncology
Background:
- The p53 protein is crucial for maintaining cell stability and preventing tumor formation.
- Mutations in the TP53 gene are found in approximately 50% of human cancers, leading to altered p53 function and promoting cancer growth.
- Mutant p53 (mutp53) can gain new cancer-promoting functions, making it a significant challenge in cancer therapy.
Purpose of the Study:
- To provide a comprehensive overview of mutant p53 (mutp53) regulation.
- To highlight the structural characteristics of mutp53 and its potential as a therapeutic target.
- To review compounds that can reactivate mutp53, aiming to advance precision cancer therapy.
Main Methods:
- Literature review integrating structural, pharmacological, and biological data on p53.
- Focus on structural studies of wild-type (wt) and mutant p53 (mutp53).
- Analysis of targeting agents designed to restore wt-like function to mutp53.
Main Results:
- Structural studies have significantly advanced the understanding of p53's role in cellular processes and disease.
- Various compounds show potential in restoring wild-type (wt)-like function to mutant p53 (mutp53), though clinical application is pending.
- Understanding mutp53 structure and reactivation mechanisms is crucial for developing novel anticancer drugs.
Conclusions:
- Targeting mutant p53 (mutp53) represents a promising strategy for cancer treatment.
- Further research into mutp53 structural traits and reactivation agents can lead to improved small molecules for precision cancer therapy.
- Developing effective p53-targeting therapies holds potential for significant advancements in treating a wide range of human cancers.
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