Research Project
6691491
DESCRIPTION (provided by applicant): p53 acts as a tumor suppressor by mediating apoptosis and growth arrest in response to a variety of stresses. On the other hand, p53 is responsible for severe damage of normal tissues during cancer therapies indicating that p53 is a determinant of cancer treatment side effects. A novel therapeutic strategy was suggested that is based on reversible pharmacological suppression of p53 to reduce tissue damage caused by chemo- and radiation therapy of p53-deficient cancers. This strategy was experimentally validated by isolation of a small molecule inhibitor of p53, pifithrin-(, that can rescue animals from lethal genotoxic stress. Ultimate goal of this program is to develop clinically useful p53 inhibitory drugs protecting tissues from side effects of cancer treatment and/or other pathological conditions associated with the activation of p53-mediated cell death. After isolation of p53 inhibitors and improvement of candidate compounds, they will be classified according to their toxicological profile and therapeutic properties in animal models. This program has already made a successful start by isolation of new p53 inhibitors by screening chemical library in a newly developed cell-based readout system. The first phase of the study is aimed at: (i) isolation and functional/structural classification of small molecules inhibiting p53 functions based on the readout allowing for the isolation of chemicals modulating p53 transactivation and (ii) establishment and validation of a new readout system making it possible to directly screen for chemicals interfering with p53-mediated apoptosis. The completion of this phase will result in isolation of potent p53 inhibitors specifically targeting p53-dependent apoptosis and will open the way for the development of lead compounds with the desirable molecular and pharmacological properties. It will strengthen intellectual property basis of the underlying concept and will make new classes of p53 inhibitors available for the academic community, thus facilitating further development of new applications of p53 inhibitors.
