2. Academic Validation
  3. 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
PMID: 23603658 DOI: 10.1038/nchembio.1246
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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