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Nat Chem Biol. 2013 Jun;9(6):390-7. doi: 10.1038/nchembio.1246. Epub 2013 Apr 21.

Structure-guided design of a selective BCL-X(L) inhibitor.

Author information

1
Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. glessene@wehi.edu.au

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.

PMID:
23603658
DOI:
10.1038/nchembio.1246
[Indexed for MEDLINE]

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