spacer Crystal structure of Bcl-xL in complex with inhibitor (Compound 3).
Primary citation
Title Structure-Guided Design of a Selective Bcl-Xl Inhibitor
Authors Lessene,; Czabotar,; Sleebs,; Zobel,; Lowes,; Adams,; Baell,; Colman,; Deshayes,; Fairbrother,; Flygare,; Gibbons,; Kersten,; Kulasegaram,; Moss,; Parisot,; Smith,; Street,; Yang,; Huang,; Watson,
Journal vol:9, pag:390 (2013), Identifiers: PubMed ID (23603658)search DOI (10.1038/nchembio.1246)
Abstract The prosurvival BCL-2 family protein BCL-XL is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-XL will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-XL-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-XL and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-XL 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-XL for their sustained growth.
MeSH terms
Other entries described in this publication 3zk6, 3zlr, 3zlo