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Gerard Zambetti, PhD
St. Jude researchers are part of a team that has synthesized a new family of small molecules designed to reactivate mutated forms of the protein p53, one of the body’s most important defenses against the development of tumors. A report on this work appears in the May 4 issue of the Journal of the American Chemical Society.
Normal p53 inhibits the growth of defective cells and triggers the process of apoptosis, or cell suicide. Without this safeguard, an abnormal cell could survive and thrive, causing cancer, according to Gerard Zambetti, PhD, Biochemistry. In addition, mutated p53 might also have a direct cancer-causing activity, he noted.
“Some forms of mutant p53 appear to be literally bent out of shape,” Zambetti said. “The aim of our project is to synthesize molecules that fold the mutant p53 proteins back into their normal shape. Since mutant forms of p53 are present in about half of all human cancers, reactivating p53 could have a major impact on health care.”
Previous researchers reported success in reactivating p53 proteins, but they used molecules that also bound to DNA—a potentially dangerous interaction that could cause mutations. In a preliminary study, Zambetti and his colleagues overcame that problem by developing compounds based on a molecule called PRIMA-1, and then simplifying that parent compound so it could be easily modified into many variations. By adding and removing different small molecules to PRIMA-1, they made a variety of compounds that could be tested for their abilities to reactivate p53 in osteosarcoma cells.
Following treatment of osteosarcoma cells in the laboratory with PRIMA-1 or with several of the compounds made by modifying PRIMA-1, the cancerous cells died.
“This work is a proof of principle that we can design drugs to selectively target cancer cells that have mutant p53 proteins in them,” Zambetti said. “These initial results have encouraged us to pursue this work further.”
The researchers are now trying to determine whether PRIMA-1 compounds kill cancer cells through reactivation of mutated p53 so that it causes apoptosis, or through some other activity, such as blocking the ability of mutated p53 to enhance cancer cell growth and survival.
Other authors of the paper include JinLing Wang of Biochemistry, as well as researchers at Northwestern University and the Laboratory of Bioorganic Chemistry at the National Institutes of Health.
Last update: May 2005