Reactivation of Mutant p53 with a New Class of Small Molecules (23079)

Novel molecules, effective at inducing apoptosis by reactivating mutant p53, have recently been synthesized by Daniel Appella et. al. These compounds facilitate p53 protein binding to DNA and activate apoptosis in transformed cells.

BACKGROUND: In healthy cells, p53 controls the integrity of cellular DNA by arresting cell proliferation, initiating cell death or mediating DNA repair in the event of DNA damage. Thus, by inducing cell death, p53 acts as a tumor suppressor by preventing a cell with damaged DNA from dividing. Many chemotherapeutic approaches aim to damage DNA and induce activation of the p53 protein and its ability to induce cellular apoptosis. However, if p53 function is blocked, such chemotherapeutic approaches are not effective, as p53 is unable to activate the apoptotic cascade. Mutations in p53 are the most common genetic abnormalities shown to be associated with human cancer. About 60% of human cancers exhibit defects in the gene as point mutations, deletions or insertions; cancers such as lung, stomach, breast, colon, liver, prostate, head and neck, esophageal, leukemia, lymphoma, ovary and bladder have been shown to contain mutations in p53.

These novel compounds induce apoptosis in cancer cells by promoting mutant p53 binding to target DNA and thus reactivating p53’s ability to act as a tumor suppressor. These compounds are designed based on the structure of PRIMA-1, a compound demonstrated to effectively bind to mutant p53; the basic structures are shown below. The investigators have already demonstrated that these compounds and derivatives of these compounds are able to induce cell death in cells containing mutant p53.

U.S. Patent No. 7,329,775

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