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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere20352
JournaleLife
Volume5
Issue numberNOVEMBER2016
DOIs
StatePublished - Nov 2 2016

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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