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Elife. 2016 Nov 2;5. pii: e20352. doi: 10.7554/eLife.20352.

Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer.

Author information

1
Department of Bioengineering, University of Washington, Seattle, United States.
2
Department of Biochemistry, University of Washington, Seattle, United States.
3
Department of Biochemistry, University of Illinois, Urbana, United States.
4
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
5
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
6
Department of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia.
7
Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Australia.
8
School of Cancer Medicine, La Trobe University, Melbourne, Australia.
9
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
10
Department of Medical Biology, University of Melbourne, Parkville, Australia.
11
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
12
Institute for Protein Design, University of Washington, Seattle, United States.
13
Department of Genome Sciences, University of Washington, Seattle, United States.
14
Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
15
Howard Hughes Medical Institute, University of Washington, Seattle, United States.

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.

KEYWORDS:

Bcl-2; cancer; cancer biology; computational biology; computational protein design; human; systems biology

PMID:
27805565
PMCID:
PMC5127641
DOI:
10.7554/eLife.20352
[Indexed for MEDLINE]
Free PMC Article

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