A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells

Nguyen, Giang Huong, Dexheimer, Thomas S., Rosenthal, Andrew S. , Chu, Wai Kit, Singh, Dharmendra Kumar, Mosedale, Georgina, Bachrati, Csanad Z., Schultz, Lena, Sakurai, Masaaki, Savitsky, Pavel, Abu, Mika, McHugh, Peter J., Bohr, Vilhelm A., Harris, Curtis C., Jadhav, Ajit, Gileadi, Opher, Maloney, David J., Simeonov, Anton and Hickson, Ian D. (2013) A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells. Chemistry & Biology, 20 (1). pp. 55-62. ISSN 1074-5521

Full content URL: http://dx.doi.org/10.1016/j.chembiol.2012.10.016

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Item Type:Article
Item Status:Live Archive


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 the toxicity of aphidicolin, and exert antiproliferative activity in cells expressing BLM, but not those lacking BLM. These data indicate that ML216 shows strong selectivity for BLM in cultured cells. We discuss the potential utility of such a BLM-targeting compound as an anticancer agent.

Keywords:Bloom syndrome, Small molecule inhibitors, RecQ helicases
Subjects:C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
Divisions:College of Science > School of Life Sciences
ID Code:7390
Deposited On:30 Jan 2013 15:42

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