A new study, led by researchers at the University of California, Irvine and the University of California, San Diego, reveals a new computationally-guided approach to identifying small molecules capable of suppressing aspects of wild-type p53 tumor suppressor function. to restore mutated p53, which plays an important role in many human cancers. This approach was both successful in vitro et in vivo. This strategy may increase the chemical diversity of p53-correcting molecules for clinical development.
The p53 tumor suppressor is one of the most powerful mechanisms used by organisms to protect themselves against cancer. Elephants have multiple copies of the p53 gene and rarely get cancer. Humans have only one copy and it is the most commonly mutated gene found in human cancer. Various therapeutic approaches are actively being pursued to target this pathway.
“Interestingly, a large proportion of p53 changes are missense mutations, where the genetic code for p53 is changed in a way that produces a different amino acid than it normally would,” said Peter Kaiser, PhD, professor and chair from the Department of Biological Chemistry at the UCI School of Medicine. “This translates into an abundance of mutant p53 protein levels in tumors that are in principle amenable to a corrective drug approach. »
posted inCellular Chemical Biology, the study identified small drug-like compounds that act through a well-defined mode of action; does not require covalent attachment, induction of redox imbalance, or metal binding; and has selective anticancer activities on tumors with p53 missense mutations. This research provides a framework for the discovery of a p53 reactivation compound that can help increase chemical diversity and improve the pharmacological properties needed to translate pharmaceutical p53 mutant reactivation to the clinic.
“This study successfully demonstrates the feasibility and efficacy of pharmaceutical reactivation of the p53 mutant,” said Kaiser. “These results are encouraging given the large number of cancer patients with p53 mutations who can benefit from these drugs. »
This study involves the application of an ensemble-based virtual screening approach, developed in the laboratory of Rommie Amaro, a professor and 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 on a panel of p53 mutants. The researchers showed that their compounds bind to mutant p53 and change the conformation of mutant p53 to wild-type structures. It restores the DNA-binding activity of p53 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 the precise mechanisms and develop highly active corrective agents for mutated p53 and future experiments are needed to optimize the pharmacological properties to progress to clinical therapeutics.
The study was supported by the National Institutes of Health and the Department of Defense.
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