Structure-guided design of a selective BCL-X-L inhibitor
Details
Publication Year 2013-06, Volume 9, Issue #6, Page 390-397
Journal Title
NATURE CHEMICAL BIOLOGY
Publication Type
Journal Article
Abstract
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.
Publisher
NATURE PUBLISHING GROUP
Keywords
SMALL-MOLECULE INHIBITOR; PROGRAMMED CELL-DEATH; PEPTIDE COMPLEX; FAMILY PROTEINS; ANTITUMOR-ACTIVITY; APOPTOSIS PATHWAY; CRYSTAL-STRUCTURE; CANCER-THERAPY; IN-VITRO; MCL-1
WEHI Research Division(s)
Chemical Biology; Molecular Genetics Of Cancer; Structural Biology
Rights Notice
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


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