spacer Crystal structure of Bcl-xL in complex with inhibitor (WEHI-539).
Primary citation
Title Structure-Guided Design of a Selective Bcl-Xl Inhibitor
Authors Lessene, G.L.search; Czabotar, P.E.search; Sleebs, B.E.search; Zobel, K.search; Lowes, K.L.search; Adams, J.M.search; Baell, J.B.search; Colman, P.M.search; Deshayes, K.search; Fairbrother, W.J.search; Flygare, J.A.search; Gibbons, P.search; Kersten, W.J.A.search; Kulasegaram, S.search; Moss, R.M.search; Parisot, J.P.search; Smith, B.J.search; Street, I.P.search; Yang, H.search; Huang, D.C.S.search; Watson, K.G.search
Journal NAT.CHEM.BIOL.search 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 3zlo, 3zk6, 3zln
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