Florian Muller, Ph.D. has proposed a novel strategy for molecular targeted therapy in cancer, exploiting vulnerabilities exposed by passenger deleted genes, an approach known as “collateral lethality”. Muller presented proof-of-principal data for one example of this strategy, where glioma cells with passenger deletion of the glycolytic enzyme, ENO1 are selectively sensitive to inhibition to its redundant homologue, ENO2. Since then, Muller’s team has explored chemical matter as a basis for generating a clinical candidate Enolase inhibitor to treat such cancers. During this work, they discovered that a natural product antibiotic of unknown mode of action termed SF2312, is a highly potent, nM-affinity inhibitor of Enolase and demonstrated that SF2312 shows strong selective toxicity towards ENO1-deleted glioma cells. Mechanistically, this is not due to specificity of SF2312 for ENO2 over ENO1, but instead, because ENO1-deleted cells have a 90% reduction in overall Enolase activity, rendering them sensitive to even low levels of pan-Enolase inhibitors. Muller’s team currently works on developing a clinical candidate Enolase inhibitor, for the treatment of glioblastoma and other cancers with deletion of ENO1 and to demonstrate the universality and utility of this therapeutic strategy to other passenger deleted genes.