Novel computationally-guided approach to identify small molecule corrective drugs for p53 hotspot mutations

A new study, led by researchers at the University of California, Irvine and the University of California, San Diego, reveals a novel computationally-guided approach to identifying small molecules capable of restoring aspects of suppressor function wild-type tumor p53 on mutated p53, which play an important role in many human cancers. This approach has been successful both in vitro and live. This strategy can 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 mutated gene found in human cancer. Various therapeutic approaches are actively pursued to target this pathway.

Interestingly, a large portion of p53 alterations are missense mutations, where the p53 genetic code is changed in a way that produces a different amino acid than it normally would. This results in an abundance of mutant p53 protein levels in tumors that are, in principle, amenable to a corrective drug approach. »


Peter Kaiser, PhD, Professor and Chair of the Department of Biological Chemistry at UCI School of Medicine

Posted in Cellular Chemical Biologythe 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 a p53 reactivation compound that can help increase chemical diversity and improve the pharmacological properties necessary to translate pharmaceutical mutant p53 reactivation to the clinic.

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

This study involved the application of an ensemble-based virtual screening approach, developed in the lab 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. This 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 exact mechanisms and develop highly active corrective drugs for mutated p53 and future experiments are needed to optimize the pharmacological properties to progress towards clinical therapeutics.

The study was supported by the National Institutes of Health and the Department of Defense.

Source:

University of California – Irvine

Journal reference:

Durairaj, G. et al. (2022) Discovery of compounds that reactivate p53 mutants in vitro and in vivo. Cellular Chemical Biology. doi.org/10.1016/j.chembiol.2022.07.003.

Sharon D. Cole