Filling a Transient Binding Pocket Reactivates Mutant Forms of the p53 Tumor Suppressor Protein

A computational method was used to match a transiently open pocket on the surface of a mutated form of the p53 tumor suppressor protein with a low molecular-weight drug that was able to fill the pocket and by doing so return the molecule to its active morphology.

The tumor suppressor p53 is the most frequently mutated gene in human cancer, and reactivation of mutant p53 by small molecules is an exciting potential cancer therapy. To this end investigators at the University of California, Irvine (USA) used an advanced computer program to screen a library of 2,298 small molecules for their potential to fill a binding pocket that is available about 5% of the time on the surface of the p53 protein between loop L1 and sheet S3 of the core domain. A paper published in the January 29, 2013, online edition of the journal Nature Communications explained that 45 of the most promising compounds were evaluated in biological assays. From these 45 compounds, only stictic acid fit into the protein pocket and reasserted the tumor-suppressing properties of the mutant p53 molecules.

Stictic acid is an aromatic organic compound that is a product of secondary metabolism in some species of lichens. It became the subject of cancer research after it was found that stictic acid extracted from Antarctic lichens had an apoptotic effect. In human osteosarcoma cells, stictic acid exhibited superior dose-dependent reactivation of p53 expression than did another reactivator, PRIMA-1.

“Stictic acid cannot be developed into a viable drug,” said contributing author Dr. Peter Kaiser, professor of biological chemistry at the University of California, Irvine. “Nonetheless, this work suggests that a comprehensive screening of small molecules with similar traits may uncover a usable compound that binds to this specific p53 pocket. The discovery and pharmaceutical development of such a compound could have a profound impact on cancer treatments. Instead of focusing on a specific form of the disease, oncologists could treat a wide spectrum of cancers, including those of the lung and breast. There is currently one group of experimental drugs - called Nutlins - that stop p53 degradation, but they do not target protein mutations as would a drug binding to the newly discovered pocket.”

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