Abstract 4753: Targeting nucleotide excision repair: Chemical synthetic lethality and biology-based combination therapy

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 4753
• Main Authors: Turchi, John J., Lee, Jiyoon, Hendricks, Jeremiah, Neher, Tracy M., Fitch, Richard W.
• Format: Journal Article
• Language: English
• Published: 15.04.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-4753

Abstract As DNA repair defects in cancer can be exploited for therapeutic benefit via synthetic lethality, new DNA repair targets and compounds to inhibit them will expand the armamentarium against cancer. While most targeted therapies involve disrupting enzyme-substrate interactions we have pursued targeting protein-DNA interactions to validate an entire new class of molecular interactions that can be targeted with small molecule drugs. We have focused on the nucleotide excision repair (NER) pathway and two proteins, the single-stranded DNA binding protein, replication protein A (RPA) and the xeroderma pigmentosum group A (XPA) protein. We have identified and developed small molecule inhibitors (SMIs) of each target. In vitro analysis of XPA SMI has led to a 50-fold increase in potency and revealed structure-activity relationships that define the important pharmacophores for XPA interaction. Both reversible and irreversible SMIs of RPA have been identified and cellular analysis of irreversible RPA SMI's revealed single agent anticancer activity at sub-micro-molar concentrations. The degree of the anticancer effect of cellular RPA inhibition varied among cancer types and was dependent on the DNA repair phenotype. Synergy between NER inhibition and cisplatin will be presented and as a function of DNA repair phenotype. These data demonstrate the ability to develop SMI of protein-DNA interactions that impact DNA repair and can be employed to increase the sensitivity of repair deficient tumors to DNA damaging therapeutics. This works was supported by NIH grant R01-CA82741 to JJT Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4753. doi:1538-7445.AM2012-4753