Abstract 3878: Newly identified p53-pathway restoring small molecule, CB002 analog #4 induces apoptosis and appears non-toxic in vivo

Abstract

Abstract The transcription factor encoding TP53 tumor suppressor gene is mutated in more than half of human cancers. TP53 accounts for therapy resistance and poor patient survival in colorectal and other cancers. Upon cellular stress, p53 protein determines cell fate through the regulation of cell senescence, cell cycle arrest, and apoptosis pathways. Distinct from other tumor-suppressors, mutated p53 can acquire a gain-of-function activity, leading to chemotherapy resistance and a more aggressive tumor phenotype. Direct therapeutic targeting of transcription factors is challenging especially when reactivation is needed; thus, to date, there are no FDA approved drugs for p53 functional restoration in tumors harboring p53 mutations. To overcome this, we have screened for small molecules capable of restoring wild-type p53 pathway signaling rather than direct physical restoration of its function. We identified a small molecule, CB002 analog #4 capable of restoring the p53 pathway in HCT116, SW480 and DLD-1 colorectal cancer cell lines as indicated by the increased expression of p53-target genes NOXA, p21 and DR5, and apoptotic markers upon treatment. We found that analog #4 enhances ethidium homodimer staining of dead cells and decreases the number of positive Ki67 staining cells in colorectal cancer patient organoids. Sub-G1 analysis demonstrated that analog #4 does not induce apoptosis in normal human fibroblasts and preliminary in vivo studies indicate that it can be safely administered to mice. We are investigating the in vivo efficacy of analog #4 in addition to its mechanism of action through micro-array experiments. Our data supports the concept that small molecules can restore the p53-pathway as a therapeutic strategy that can be translated into a clinical setting. Citation Format: Liz J. Hernandez Borrero, Avital Lev, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry. Newly identified p53-pathway restoring small molecule, CB002 analog #4 induces apoptosis and appears non-toxic in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3878.