A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells.
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.
Department of Medical Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Giang Huong
GH
Nguyen
Thomas S
TS
Dexheimer
Andrew S
AS
Rosenthal
Wai Kit
WK
Chu
Dharmendra Kumar
DK
Singh
Georgina
G
Mosedale
Csanád Z
CZ
Bachrati
Lena
L
Schultz
Masaaki
M
Sakurai
Pavel
P
Savitsky
Mika
M
Abu
Peter J
PJ
McHugh
Vilhelm A
VA
Bohr
Curtis C
CC
Harris
Ajit
A
Jadhav
Opher
O
Gileadi
David J
DJ
Maloney
Anton
A
Simeonov
Ian D
ID
Hickson
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D043171:Chromosomal Instability / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D053484:RecQ Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D004247:DNA; C097151:Bloom syndrome protein; D053484:RecQ Helicases