1. Academic Validation
  2. Structure-guided design of a selective BCL-X(L) inhibitor

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

  • Nat Chem Biol. 2013 Jun;9(6):390-7. doi: 10.1038/nchembio.1246.
Guillaume Lessene 1 Peter E Czabotar Brad E Sleebs Kerry Zobel Kym N Lowes Jerry M Adams Jonathan B Baell Peter M Colman Kurt Deshayes Wayne J Fairbrother John A Flygare Paul Gibbons Wilhelmus J A Kersten Sanji Kulasegaram Rebecca M Moss John P Parisot Brian J Smith Ian P Street Hong Yang David C S Huang Keith G Watson
Affiliations

Affiliation

  • 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.

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