eLife (Nov 2016)
Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer
- Stephanie Berger,
- Erik Procko,
- Daciana Margineantu,
- Erinna F Lee,
- Betty W Shen,
- Alex Zelter,
- Daniel-Adriano Silva,
- Kusum Chawla,
- Marco J Herold,
- Jean-Marc Garnier,
- Richard Johnson,
- Michael J MacCoss,
- Guillaume Lessene,
- Trisha N Davis,
- Patrick S Stayton,
- Barry L Stoddard,
- W Douglas Fairlie,
- David M Hockenbery,
- David Baker
Affiliations
- Stephanie Berger
- ORCiD
- Department of Bioengineering, University of Washington, Seattle, United States
- Erik Procko
- Department of Biochemistry, University of Washington, Seattle, United States; Department of Biochemistry, University of Illinois, Urbana, United States
- Daciana Margineantu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
- Erinna F Lee
- Department of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Betty W Shen
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
- Alex Zelter
- Department of Biochemistry, University of Washington, Seattle, United States
- Daniel-Adriano Silva
- Department of Biochemistry, University of Washington, Seattle, United States; Institute for Protein Design, University of Washington, Seattle, United States
- Kusum Chawla
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
- Marco J Herold
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Jean-Marc Garnier
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Richard Johnson
- Department of Genome Sciences, University of Washington, Seattle, United States
- Michael J MacCoss
- Department of Genome Sciences, University of Washington, Seattle, United States
- Guillaume Lessene
- ORCiD
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
- Trisha N Davis
- ORCiD
- Department of Biochemistry, University of Washington, Seattle, United States
- Patrick S Stayton
- Department of Bioengineering, University of Washington, Seattle, United States
- Barry L Stoddard
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
- W Douglas Fairlie
- Department of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- David M Hockenbery
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
- David Baker
- ORCiD
- Department of Biochemistry, University of Washington, Seattle, United States; Institute for Protein Design, University of Washington, Seattle, United States; Howard Hughes Medical Institute, University of Washington, Seattle, United States
- DOI
- https://doi.org/10.7554/eLife.20352
- Journal volume & issue
-
Vol. 5
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
