학술논문
Structure-guided design of a selective BCL-XL inhibitor.
Document Type
Article
Author
Lessene, Guillaume; Czabotar, Peter E; Sleebs, Brad E; Zobel, Kerry; Lowes, Kym N; Adams, Jerry M; Baell, Jonathan B; Colman, Peter M; Deshayes, Kurt; Fairbrother, Wayne J; Flygare, John A; Gibbons, Paul; Kersten, Wilhelmus J A; Kulasegaram, Sanji; Moss, Rebecca M; Parisot, John P; Smith, Brian J; Street, Ian P; Yang, Hong; Huang, David C S
Source
Subject
*CANCER cells
*ANTINEOPLASTIC agents
*PROTEINS
*CANCER treatment
*TISSUES
*PHARMACEUTICAL chemistry
*
*
*
*
*
Language
ISSN
1552-4450
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. [ABSTRACT FROM AUTHOR]