The Bloom’s syndrome protein, BLM, is a member of the conserved RecQ helicase family. Although cell lines lacking BLM exist, these exhibit progressive genomic instability that makes distinguishing primary from secondary effects of BLM loss problematic. In order to be able to acutely disable BLM function in cells, we undertook a high throughput screen of a chemical compound library for small molecule inhibitors of BLM. We present ML216, a potent inhibitor of the DNA unwinding activity of BLM. ML216 shows cell-based activity, and can induce sister chromatid exchanges, enhance to the toxicity of aphidicolin and exert anti-proliferative activity in cells expressing BLM, but not in those lacking BLM. These data indicate that ML216 shows strong selectively for BLM in cultured cells. We discuss the potential utility of such a BLM-targeting compound as an anticancer agent.

Background: The nucleases hSNM1A and hSNM1B are implicated in DNA interstrand cross-link repair.Results: hSNM1A and hSNM1B were biochemically characterized using undamaged and cross-linked DNA. A real-time assay for the nucleases suitable for inhibitor identification was developed.Conclusion: Preferential hSNM1A activation by high molecular weight and cross-linked DNA was observed.Significance: This work provides a basis for hSNM1A inhibitor development for improved cancer therapy.