A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells

Giang Huong Nguyen; 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

doi:10.1016/j.chembiol.2012.10.016

A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells

Giang Huong Nguyen, 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

91 Citations (Scopus)

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.

Original language	English
Journal	Chemistry & Biology
Volume	20
Issue number	1
Pages (from-to)	55-62
Number of pages	8
DOIs	https://doi.org/10.1016/j.chembiol.2012.10.016
Publication status	Published - 24 Jan 2013

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Nguyen, G. H., Dexheimer, T. S., Rosenthal, A. S., Chu, W. K., Singh, D. K., Mosedale, G., Bachrati, C. Z., Schultz, L., Sakurai, M., Savitsky, P., Abu, M., McHugh, P. J., Bohr, V. A., Harris, C. C., Jadhav, A., Gileadi, O., Maloney, D. J., Simeonov, A., & Hickson, I. D. (2013). A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells. Chemistry & Biology, 20(1), 55-62. https://doi.org/10.1016/j.chembiol.2012.10.016

Nguyen, GH, Dexheimer, TS, Rosenthal, AS, Chu, WK, Singh, DK, Mosedale, G, Bachrati, CZ, Schultz, L, Sakurai, M, Savitsky, P, Abu, M, McHugh, PJ, Bohr, VA, Harris, CC, Jadhav, A, Gileadi, O, Maloney, DJ, Simeonov, A & Hickson, ID 2013, 'A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells', Chemistry & Biology, vol. 20, no. 1, pp. 55-62. https://doi.org/10.1016/j.chembiol.2012.10.016

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title = "A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells",

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.",

author = "Nguyen, {Giang Huong} and Dexheimer, {Thomas S} and Rosenthal, {Andrew S} and Chu, {Wai Kit} and Singh, {Dharmendra Kumar} and Georgina Mosedale and Bachrati, {Csan{\'a}d Z} and Lena Schultz and Masaaki Sakurai and Pavel Savitsky and Mika Abu and McHugh, {Peter J} and Bohr, {Vilhelm A} and Harris, {Curtis C} and Ajit Jadhav and Opher Gileadi and Maloney, {David J} and Anton Simeonov and Hickson, {Ian D}",

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T1 - A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells

AU - Nguyen, Giang Huong

AU - Dexheimer, Thomas S

AU - Rosenthal, Andrew S

AU - Chu, Wai Kit

AU - Singh, Dharmendra Kumar

AU - Mosedale, Georgina

AU - Bachrati, Csanád Z

AU - Schultz, Lena

AU - Sakurai, Masaaki

AU - Savitsky, Pavel

AU - Abu, Mika

AU - McHugh, Peter J

AU - Bohr, Vilhelm A

AU - Harris, Curtis C

AU - Jadhav, Ajit

AU - Gileadi, Opher

AU - Maloney, David J

AU - Simeonov, Anton

AU - Hickson, Ian D

PY - 2013/1/24

Y1 - 2013/1/24

N2 - 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.

AB - 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.

U2 - 10.1016/j.chembiol.2012.10.016

DO - 10.1016/j.chembiol.2012.10.016

M3 - Journal article

C2 - 23352139

SN - 2451-9448

VL - 20

SP - 55

EP - 62

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 1

ER -

A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells

Abstract

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