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

被引：128

作者：

Giang Huong Nguyen ^{[1
,2
]}

Dexheimer, Thomas S. ^{[3
]}

Rosenthal, Andrew S. ^{[3
]}

Chu, Wai Kit ^{[4
]}

Singh, Dharmendra Kumar ^{[6
]}

Mosedale, Georgina ^{[1
]}

Bachrati, Csanad Z. ^{[1
]}

Schultz, Lena ^{[3
]}

Sakurai, Masaaki ^{[3
]}

Savitsky, Pavel ^{[5
]}

Abu, Mika ^{[1
]}

McHugh, Peter J. ^{[1
]}

Bohr, Vilhelm A. ^{[6
]}

Harris, Curtis C. ^{[2
]}

Jadhav, Ajit ^{[3
]}

Gileadi, Opher ^{[5
]}

Maloney, David J. ^{[3
]}

Simeonov, Anton ^{[3
]}

Hickson, Ian D. ^{[1
,4
]}

机构：

[1] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Dept Med Oncol, Oxford OX3 9DS, England

[2] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[3] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20892 USA

[4] Univ Copenhagen, Dept Cellular & Mol Med, Nordea Ctr Hlth Aging, DK-2200 Copenhagen N, Denmark

[5] Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ, England

[6] NIA, NIH, Baltimore, MD 21224 USA

来源：

CHEMISTRY & BIOLOGY | 2013年 / 20卷 / 01期

基金：

加拿大创新基金会; 英国惠康基金;

关键词：

BLOOMS-SYNDROME HELICASE; SYNDROME GENE-PRODUCT; RECQ HELICASES; TOPOISOMERASE-III; D-LOOPS; DNA; INSTABILITY; TELOMERASE; SUBSTRATE; INTERACTS;

D O I：

10.1016/j.chembiol.2012.10.016

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：55 / 62

页数：8

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