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.

Structural and drug targeting insights on mutant p53 / Gomes, A. S.; Ramos, H.; Inga, A.; Sousa, E.; Saraiva, L.. - In: CANCERS. - ISSN 2072-6694. - 13:13(2021), pp. 334401-334438. [10.3390/cancers13133344]

Structural and drug targeting insights on mutant p53

Inga A.;
2021-01-01

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.
2021
13
Gomes, A. S.; Ramos, H.; Inga, A.; Sousa, E.; Saraiva, L.
Structural and drug targeting insights on mutant p53 / Gomes, A. S.; Ramos, H.; Inga, A.; Sousa, E.; Saraiva, L.. - In: CANCERS. - ISSN 2072-6694. - 13:13(2021), pp. 334401-334438. [10.3390/cancers13133344]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/333844
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