| Despite the recent advent of molecularly-targeted agents, radiation therapy and DNA-damaging chemotherapy remain essential tools in the treatment of human cancers, particularly solid tumors. Innate or acquired resistance to these therapies represents a major clinical challenge in oncology. The development of small molecules that sensitize tumor cells to established therapies is therefore an attractive approach to extend survival and quality of life in patients. Using a high-throughput synthetic lethality screen of small molecule libraries, we have identified a novel class of DNA double-strand break repair inhibitors that exhibits potent synthetic lethal activity in the setting of DNA damage response and DNA repair defects. This dissertation details the identification and biological characterization of these molecules, as well as investigation of their potential for clinical translation. Much of the work herein utilizes the current lead compound of this aryl sulfonamide series, YU238259. YU238259 specifically inhibits homology-dependent DNA repair (HDR), but not non-homologous end-joining (NHEJ). This inhibition of HDR yields potent synthetic lethality across a spectrum of tumor types with common DNA repair mutations and is synergistic with ionizing radiation, etoposide, and PARP inhibition, and that this synergism is heightened in the setting of BRCA2deficiency. Mouse studies demonstrate the utility of these compounds in slowing tumor growth of BRCA2-deficient ovarian cancer and PTEN-deficient melanoma. |
