Abstract 2188: A screen to identify novel p53 family member activity-restoring compounds with a focus on p73.

Abstract

Abstract Tumor suppressor p53 family regulates gene transcription, and thereby cell cycle, apoptosis, metabolism and other processes. The p53 gene is found mutated in over 50% of all human cancers, and it has been of great interest to identify drugs that can restore p53 function. While p53 can display a wide variety of mutations, which potentially could complicate function restoration therapy, family member p73 gene mutation is rare. Therefore, we sought to identify novel compounds that are able to restore the activity of the p53 family, with a focus on p73 dependency in the presence of mutant p53. To this end, a functional cell-based screening assay was set up for cancer cell death-inducing small molecules that activate p53 pathway-dependent gene transcription. SW480 colon carcinoma cells, which carry R273H/R309S mutations in p53, and stably express a p53 family-responsive luciferase construct, were utilized, with parental cells and cells displaying stable knockdown of p73 being subjected to compounds from NCI Diversity Set 3. This set contains about 1600 compounds that are relatively well characterized and structurally rigid. After various treatment periods, p53 activity was assessed, as well as cell viability. Subsequently, a total of 26 compounds were selected for further investigation and validation. Follow up studies will include dose and time courses for p53 family activation and viability in a variety of cell lines that are wild-type, mutant or null for p53. Also mechanistic studies and cellular assays will be performed, with the hopes to identify novel drugs that are able to restore activity of the p53 family, and subsequent cancer cell death, and thus providing novel candidates for the treatment of human cancer. Citation Format: Antonius P. van den Heuvel, Wenge Wang, Levy Kopelovich, Wafik S. El-Deiry. A screen to identify novel p53 family member activity-restoring compounds with a focus on p73. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2188. doi:10.1158/1538-7445.AM2013-2188