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Structure-guided design of a selective BCL-X-L inhibitor


Lessene, G; Czabotar, PE; Sleebs, BE; Zobel, K; Lowes, KN; Adams, JM; Baell, JB; Colman, PM; Deshayes, K; Fairbrother, WJ; Flygare, JA; Gibbons, P; Kersten, WJA; Kulasegaram, S; Moss, RM; Parisot, JP; Smith, BJ; Street, IP; Yang, H; Huang, DCS; Watson, KG
2013-06
NATURE CHEMICAL BIOLOGY
Journal Article
9
6
390-397
The prosurvival BCL-2 family protein BCL-X-L is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X-L will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X-L-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X-L and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X-L and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X-L from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X-L for their sustained growth.
NATURE PUBLISHING GROUP
SMALL-MOLECULE INHIBITOR; PROGRAMMED CELL-DEATH; PEPTIDE COMPLEX; FAMILY PROTEINS; ANTITUMOR-ACTIVITY; APOPTOSIS PATHWAY; CRYSTAL-STRUCTURE; CANCER-THERAPY; IN-VITRO; MCL-1
Chemical Biology; Molecular Genetics of Cancer; Structural Biology
10.1038/NCHEMBIO.1246
Refer to article for additional funding acknowledgements
Copyright © 2013, Rights Managed by Nature Publishing Group, in accordance with the copyright policy of the publisher authors version will be available for download 6 months after publication

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Creation Date 2013-06-01 12:00:00 Last Modified 2015-03-24 11:04:08