Flap endonuclease inhibitors discovered in this screen recapitulated synthetic lethal interactions between FEN1 and each of CDC4 and MRE11A, demonstrating that evolutionarily conserved genetic interactions in a core cellular process, such as the maintenance of genomic stability, can be exploited as a means to inhibit the proliferation of tumor cells carrying specific and cancer-relevant mutations. Here, ALOX5AP is linked to neoplasm.