Are p53 inhibitors potentially useful therapeutics?

Abstract

The tumor-suppressor protein p53 is an intracellular protein critical in many biochemical cascades leading to cell death via apoptosis pathway or cell survival by arresting the cell cycle. Based on recent studies, which have characterized chemical inhibitors of p53 in the cancer therapy field as well in the pathogenesis of stroke and neurodegenerative disorders, this review concentrates on the development of drugs that inhibit p53 and their possible use as novel strategies for combating neurodegenerative diseases, cancer, and eventually HIV infection. Emphasis is mainly focussed on pifithrin-α derivatives, which appear to be the most efficient p53 inactivators known to date since no such drugs are currently approved. Pifithrin-α antagonises p53 at the post-transcriptional level. The precise mechanism through which their effects are achieved, either by direct interaction of p53 or via indirect binding, remains to be elucidated. Moreover, Pft-α derivatives are cyclized in situ in biological media into their corresponding dehydrated cyclic forms. These cyclic forms, also p53 inactivators, could represent new interesting scaffolds useful in the therapeutic treatment of p53-related disease. Drug Dev Res 65:43–49, 2005. © 2005 Wiley-Liss, Inc.