Human cancers are often characterized by deficiencies in DNA repair arising either from loss of heterozygosity at DNA repair gene loci or from DNA repair gene silencing. Pharmacologic agents that exhibit preferential cytotoxicity to DNA repair-deficient cells while minimizing damage to repair-proficient healthy tissue may therefore provide a valuable tool in the oncology clinic. In collaboration with the Yale Center for Molecular Discovery, we have used high-throughput screening to identify a novel class of small molecules that demonstrate synthetic lethality with inactivation of the homology-dependent DNA repair factors BRCA2 and FANCD2. This effect appears to result from inhibition of an early step in the recognition and repair of DNA double-strand breaks. Additionally, the compounds sensitize human cancer cell lines to treatment with ionizing radiation and clinically-relevant chemotherapy agents. We are currently in the process of identifying the cellular target(s) of these drugs and assaying their ability to inhibit tumor growth /in vivo/, both alone and in combination regimens.