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-a derivatives, which appear to be the most efficient p53 inactivators known to date since no such drugs are currently approved. Pifithrin-a 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-a 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. c 2005 Wiley-Liss, Inc.

Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains

“…In addition to its important tumor suppressor role, hyperactive p53 is implicated in Alzheimer’s disease, Parkinson’s disease, spinal cord diseases, multiple sclerosis, ischemic brain injury, infectious and auto-immune diseases, and myocardial ischemia. − Thus, inhibitors of p53 activity represent potential points of intervention in multiple diseases.…”

Chemogenomics for drug discovery: clinical molecules from open access chemical probes

“…Whilst involved in the suppression of tumour formation, p53 has also been shown to mediate excessive apoptotic death in normal cells following cancer therapy. 94 As well as this, its overactivity has been implicated in a variety of neurodegenerative and cardiovascular diseases, [95][96][97][98][99][100] suggesting its inhibition may be of therapeutic value.…”

Enhancement of Chemotherapeutic Efficacy by Small Molecule Inhibition of NF-κ B and Checkpoint Kinases

“…Essentially, the checkpoint kinases phosphorylate one or more of the Cdc25 proteins that results in their inactivation and degradation, thus preventing the Cdc25 proteins to translocate into the nucleus and enable cell cycle progression [219]. The tumor suppressor protein p53 is responsible for arresting the cell cycle and inducing apoptosis [220].…”