A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells
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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, Csanád 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; Hickson, Ian D.
In: Chemistry & Biology, Vol. 20, No. 1, 24.01.2013, p. 55-62.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
N1 - Copyright © 2013 Elsevier Ltd. All rights reserved.
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
VL - 20
SP - 55
EP - 62
JO - Chemistry and Biology
JF - Chemistry and Biology
SN - 2451-9448
IS - 1
ER -
ID: 44688582