Discovery of ML216, a Small Molecule Inhibitor of Bloom (BLM) Helicase

BLM helicase is a DNA unwinding enzyme critical in DNA repair via the homologous recombination (HR) pathway. Mutations of the BLM gene result in diminished BLM helicase activity and can cause Bloom’s Syndrome, which is characterized by a long list of phenotypes, including predisposition to cancers. Similar to other DNA repair enzymes, inhibition of BLM helicase results in sensitization of tumor cells to conventional cancer therapies, such as camptothecin. Currently, there are no known small molecule inhibitors of BLM helicase; thus, the discovery of a novel small molecule inhibitor would help define the mechanism of action of the enzyme and provide a basis for future development of inhibitors and cancer therapeutics. The first-in-class probe molecule described herein (ML216) displays low micromolar potency and selectivity over related helicases, such as RECQ1, RECQ5, and UvrD helicases. This probe also inhibits cell proliferation of BLM-proficient fibroblast cells (PSNF5) while having only minimal effects on BLM-deficient fibroblast cells (PSNG13), indicating on-target activity in a cellular context. In addition, the probe molecule increases the frequency of sister chromatid exchanges, a diagnostic cellular phenotype consistent with the absence of a functional BLM protein.