2. Academic Validation
  3. A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells

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

  • Chem Biol. 2013 Jan 24;20(1):55-62. doi: 10.1016/j.chembiol.2012.10.016.
Giang Huong Nguyen 1,  Thomas S Dexheimer,  Andrew S Rosenthal,  Wai Kit Chu,  Dharmendra Kumar Singh,  Georgina Mosedale,  Csanád Z Bachrati,  Lena Schultz,  Masaaki Sakurai,  Pavel Savitsky,  Mika Abu,  Peter J McHugh,  Vilhelm A Bohr,  Curtis C Harris,  Ajit Jadhav,  Opher Gileadi,  David J Maloney,  Anton Simeonov,  Ian D Hickson
Affiliations

Affiliation

  • 1 Department of Medical Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
PMID: 23352139 DOI: 10.1016/j.chembiol.2012.10.016
Abstract

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.

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