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New Study Unveils Computerized Approach to Suppress Cancer Tumor Growth

Graphic abstract. Credit: Geetha Durairaj et al, Cell Chemical Biology (2022). DOI: 10.116/j.chembiol.2022.07.003

A new study, led by researchers from the University of California, Irvine and the University of California, San Diego, reveals a novel computerized approach to identify small molecules that can restore aspects of the wild-type p53 tumor suppressor function to mutated p53, which is an important play a role in many human cancers. This approach was successful both in vitro and in vivo. This strategy may increase the chemical diversity of p53 corrector molecules for clinical development.

The tumor suppressor p53 is one of the most powerful mechanisms that organisms use to protect themselves against cancer. Elephants have multiple copies of the p53 gene and rarely develop cancer. Humans have only one copy and it is the most mutated gene found in human cancer. Various therapeutic approaches are actively being pursued to address this pathway.

“Interestingly, a large proportion of p53 changes are missense mutations, where the genetic code of the p53 is altered in a way that produces a different amino acid than it normally would,” explained Peter Kaiser, Ph.D., professor and chair of the Department of Biological Chemistry at the UCI School of Medicine. “This results in an abundance of mutant p53 protein levels in tumors that are basically amenable to a corrector drug approach.”

Published in Cell Chemical Biology, the study identified small drug-like compounds that act through a well-defined mode of action; do not require covalent attachment, induction of redox imbalance, or metal bonding; and have selective anticancer activities on tumors with p53 missense mutations. This research provides a framework for the discovery of p53 reactivation compounds that can help increase chemical diversity and enhance the pharmacological properties necessary for the translation of pharmaceutical p53 mutant reactivation to the clinic.

“This study successfully demonstrates the feasibility and efficacy of pharmaceutical reactivation of mutant p53,” Kaiser said. “These findings are encouraging given the large number of cancer patients with p53 mutations who could benefit from such drugs.”

This study involved the application of an ensemble-based virtual screening approach developed in the lab of Rommie Amaro, professor and endowed chair in the Department of Chemistry and Biochemistry at UC San Diego, which has the potential to identify compounds with increased cancer-killing potential. and with a broad spectrum of activity across a panel of p53 mutants. The researchers showed that their compounds bind mutant p53 and change the conformation of mutant p53 into wild-type-like structures. This restores p53 DNA binding activity to activate the p53 transcriptional response, which in turn prevents tumor progression in mouse models, selectively for tumors with a p53 missense mutation.

Challenges remain to define exact mechanisms and develop highly active corrector drugs for mutated p53 and future experiments are needed to optimize the pharmacological properties to advance towards clinical therapies.


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More information:
Geetha Durairaj et al, Discovery of compounds that reactivate p53 mutants in vitro and in vivo, Cell Chemical Biology (2022). DOI: 10.116/j.chembiol.2022.07.003

Provided by the University of California, Irvine

Quote: New Study Reveals Computer-Based Approach to Suppressing Cancer Tumor Growth (2022, Aug. 10) retrieved Aug. 10, 2022 from https://phys.org/news/2022-08-reveals-computation-guided-approach-suppressing-cancer. html

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