Nguyen, Giang Huong4; Dexheimer, Thomas S4; Rosenthal, Andrew S4; Chu, Wai Kit5; Singh, Dharmendra Kumar4; Mosedale, Georgina4; Bachrati, Csanád Z4; Schultz, Lena4; Sakurai, Masaaki4; Savitsky, Pavel4; Abu, Mika4; McHugh, Peter J4; Bohr, Vilhelm A3; Harris, Curtis C4; Jadhav, Ajit4; Gileadi, Opher4; Maloney, David J4; Simeonov, Anton4; Hickson, Ian D5
1 Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Københavns Universitet2 Section I. Center for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 Molecular Aging Program, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet4 unknown5 Section I. Center for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Chemistry and Biology, 2013, Vol 20, Issue 1, p. 55-62