Structure-guided design of a selective BCL-XL inhibitor

A high-throughput chemical screen followed by structure-guided chemical design leads to the first potent and selective small-molecule BCL-X L inhibitor. The prosurvival BCL-2 family protein BCL-X L is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer thera...

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Published inNature chemical biology Vol. 9; no. 6; pp. 390 - 397
Main Authors Lessene, Guillaume, Czabotar, Peter E, Sleebs, Brad E, Zobel, Kerry, Lowes, Kym N, Adams, Jerry M, Baell, Jonathan B, Colman, Peter M, Deshayes, Kurt, Fairbrother, Wayne J, Flygare, John A, Gibbons, Paul, Kersten, Wilhelmus J A, Kulasegaram, Sanji, Moss, Rebecca M, Parisot, John P, Smith, Brian J, Street, Ian P, Yang, Hong, Huang, David C S, Watson, Keith G
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.06.2013
Nature Publishing Group
Subjects
631/154/309/2420
631/80/82
631/92/96
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cancer
Cell Biology
Chemistry
Chemistry/Food Science
Drug therapy
Gene expression
Proteins
Tumors
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Summary:A high-throughput chemical screen followed by structure-guided chemical design leads to the first potent and selective small-molecule BCL-X L inhibitor. 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.
ISSN:1552-4450
1552-4469
DOI:10.1038/nchembio.1246