Abstract C58: Small molecule inhibitors targeting the interaction of xeroderma pigmentosum group A protein with cisplatin-damaged DNA

Abstract

Abstract Targeting DNA repair and the DNA damage response for cancer therapy has recently gained increasing attention with inhibitors of the PI3-K-like kinases in early stage clinical trials. The utility of DNA repair inhibitors can be expanded by their use in combination treatment with DNA damaging chemotherapeutics including cisplatin. We have focused on directly targeting the DNA repair pathway responsible for repairing platinum-induced DNA damage, nucleotide excision repair (NER). We have selected the molecular target XPA, whose role is in the identification and verification of the sites of DNA damage. Clinical validation of XPA has been obtained where high XPA expression in lung, ovarian and lung cancer results in decreased efficacy of platinum therapy. We report the continued development of the X80 class of XPA small molecule inhibitors. In a two-step, iterative process we have identified critical structure activity relationships that have resulted in a 100-fold increase in potency with in vitro IC50 values below 1μM. Analyses of the SARs define the chemical and structural features that impact the interaction with XPA, cellular permeability and contribute to selectivity. Data demonstrate that the X80 class of inhibitors do not interact with DNA but directly bind the XPA protein. Recent production of a sub-fragment of the XPA protein will allow the identification of the direct binding domain to enable continued structure-based design of more potent XPA inhibitors. Supported by NIH grants R01CA180710 and R41CA162648 to JJT. Citation Format: Pamela S. VanderVere-Carozza, Navnath Gavande, Akaash Mishra, John J. Turchi. Small molecule inhibitors targeting the interaction of xeroderma pigmentosum group A protein with cisplatin-damaged DNA. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C58.