Structure-guided design of a selective BCL-XL inhibitor
- 21 April 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 9 (6), 390-397
- https://doi.org/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.Keywords
This publication has 57 references indexed in Scilit:
- Deciphering the rules of programmed cell death to improve therapy of cancer and other diseasesThe EMBO Journal, 2011
- The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapyCell Death & Differentiation, 2011
- Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activityThe Lancet Oncology, 2010
- The landscape of somatic copy-number alteration across human cancersNature, 2010
- Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain BaxProceedings of the National Academy of Sciences of the United States of America, 2008
- Reaching for high-hanging fruit in drug discovery at protein–protein interfacesNature, 2007
- Structural insights into the degradation of Mcl-1 induced by BH3 domainsProceedings of the National Academy of Sciences of the United States of America, 2007
- Embedded together: The life and death consequences of interaction of the Bcl-2 family with membranesApoptosis, 2007
- The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralizedCancer Cell, 2006
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997