Abstract 3524: Structure-based molecular docking of DNA polymerase β as a novel target for chemotherapeutic intervention of colorectal cancer

Abstract

Abstract Colorectal cancer is the third most common cancer and the second most common cause of cancer related deaths worldwide. In the year 2010, an estimated 102,900 new colorectal cases will be diagnosed and 51,370 deaths will occur in the United States only. Chemoprevention presents a major strategy for the medical management of colorectal cancer risk. Most drugs used for colorectal cancer therapy induce DNA alkylation damage, which are primarily repaired by the base excision repair (BER) pathway. Thus, blockade of BER pathway is an attractive option to inhibit the spread of colorectal cancer. Here we used structure-based molecular docking of DNA polymerase β (Pol-β) and identified a potent anti-Pol-β compound NSC-124854. Our aim was to examine whether NSC-124854 could enhance the therapeutic efficacy of DNA-alkylating agent, Temozolomide (TMZ), by blocking BER. First, we determined the specificity of NSC-124854 for Pol-β by using in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single nucleotide (SN)- and long-patch (LP)-BER. Second, we determined the effect of NSC-124854 on the cytotoxicity of TMZ to mismatch repair (MMR)-deficient and MMR-proficient colon cancer cells by using in vitro clonogenic assays. Third, we used female homozygous SCID mice as a pre-clinical xenograft model to determine the effect of NSC-124854 on the in vivo tumor growth inhibition of MMR-deficient and MMR-proficient colonic tumors in mice. Our data showed that NSC-124854 elicit specificity to Pol-β and blocked Pol-β-directed SN- and LP-BER activities in vitro reconstituted system. Furthermore, NSC-124854 effectively induced the sensitivity of TMZ to MMR-deficient and MMR-proficient colon cancer cells both in vitro cell culture system and in vivo mouse model. Our findings suggest a potential novel strategy for the development of highly specific, and thus safer structure-based inhibitor(s) for the prevention of colonic tumor progression. This work has been supported by NCI/NIH grants (R01 CA-097031 and CA-100247) to SN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3524. doi:10.1158/1538-7445.AM2011-3524