Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer
- University of Washington, United States
- Fred Hutchinson Cancer Research Center, United States
- LaTrobe Institute for Molecular Science, Australia
- The Walter and Eliza Hall Institute of Medical Research, Australia
Abstract
Many cancers overexpress one or more of the six human pro-survival BCL2 family proteins to evade apoptosis. To determine which BCL2 protein or proteins block apoptosis in different cancers, we computationally designed three-helix bundle protein inhibitors specific for each BCL2 pro-survival protein. Following in vitro optimization, each inhibitor binds its target with high picomolar to low nanomolar affinity and at least 300-fold specificity. Expression of the designed inhibitors in human cancer cell lines revealed unique dependencies on BCL2 proteins for survival which could not be inferred from other BCL2 profiling methods. Our results show that designed inhibitors can be generated for each member of a closely-knit protein family to probe the importance of specific protein-protein interactions in complex biological processes.
Data availability
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Computationally designed, high specificity inhibitors delineate the roles of BCL2 family proteins in cancerPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE80194).
Article and author information
Author details
Funding
National Institutes of Health (P41GM103533)
- Stephanie Berger
- Erik Procko
- David Baker
Australian Research Council (FT150100212)
- Erinna F Lee
National Institutes of Health (R01 GM115545)
- Betty W Shen
- Barry L Stoddard
National Institutes of Health (R01 CA158921-04)
- Daciana Margineantu
- David M Hockenbery
Defense Threat Reduction Agency (HDTRA1-10-0040)
- Stephanie Berger
- Erik Procko
- David Baker
Howard Hughes Medical Institute (HHMI-027779)
- Stephanie Berger
- Erik Procko
- David Baker
National Science Foundation (Graduate Research Fellowship Program)
- Stephanie Berger
Worldwide Cancer Research (15-0025)
- Erinna F Lee
- W Douglas Fairlie
Cancer Council Victoria (1057949)
- Erinna F Lee
- W Douglas Fairlie
Pew Charitable Trusts
- Daniel-Adriano Silva
Consejo Nacional de Ciencia y Tecnología
- Daniel-Adriano Silva
National Health and Medical Research Council (1024620)
- Erinna F Lee
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Yibing Shan, DE Shaw Research, United States
Version history
- Received: August 4, 2016
- Accepted: November 1, 2016
- Accepted Manuscript published: November 2, 2016 (version 1)
- Version of Record published: November 29, 2016 (version 2)
- Version of Record updated: December 20, 2016 (version 3)
Copyright
© 2016, Berger et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer
eLife 5:e20352.
https://doi.org/10.7554/eLife.20352
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