Journal article
Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer
S Berger, E Procko, D Margineantu, EF Lee, BW Shen, A Zelter, DA Silva, K Chawla, MJ Herold, JM Garnier, R Johnson, MJ Maccoss, G Lessene, TN Davis, PS Stayton, BL Stoddard, WD Fairlie, DM Hockenbery, D Baker
Elife | ELIFE SCIENCES PUBLICATIONS LTD | Published : 2016
DOI: 10.7554/eLife.20352
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 eac..
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Awarded by National Cancer Institute
Funding Acknowledgements
National Institutes of Health P41GM103533 Stephanie Berger Erik Procko David BakerDefense Threat Reduction Agency HDTRA1-10-0040 Stephanie Berger Erik Procko David BakerHoward Hughes Medical Institute HHMI-027779 Stephanie Berger Erik Procko David BakerNational Science Foundation Graduate Research Fellowship Program Stephanie BergerWorldwide Cancer Research 15-0025 Erinna F Lee W Douglas FairlieCancer Council Victoria 1057949 Erinna F Lee W Douglas FairliePew Charitable Trusts Daniel-Adriano SilvaConsejo Nacional de Ciencia y Tecnologia Daniel-Adriano SilvaNational Health and Medical Research Council 1024620 Erinna F LeeAustralian Research Council FT150100212 Erinna F LeeNational Institutes of Health R01 GM115545 Betty W Shen Barry L StoddardNational Institutes of Health R01 CA158921-04 Daciana Margineantu David M HockenberyVictorian Government, Australia Operational Infrastructure Support Program Erinna F Lee W Douglas FairlieThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.