The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

Stewart, Michelle L; Fire, Emiko; Keating, Amy E; Walensky, Loren D

doi:10.1038/nchembio.391

Cited by 418Cell death mechanisms and regulationChemical Synthesis and AnalysisCancer-related Molecular Pathways

The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

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Stewart, Michelle L, Fire, Emiko, Keating, Amy E, Walensky, Loren D·2010·Nature Chemical Biology

DOI 10.1038/nchembio.391PMC PMC3033224

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Abstract

The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of stabilized alpha-helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature's solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition.

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[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475 · see citing works
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
Cell Death
Danial, N. N., & Korsmeyer, S. J. (2004) · Cell · doi:10.1016/s0092-8674(04)00046-7 · Cited by 4,651 · see citing works
PHENIX : building new software for automated crystallographic structure determination
Adams, P. D., Grosse-Kunstleve, R. W., Hung, L.-W., Ioerger, T. R., McCoy, A. J., Moriarty, N. W., Read, R. J., Sacchettini, J. C., Sauter, N. K., & Terwilliger, T. C. (2002) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444902016657 · Cited by 4,361 · see citing works
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017 · see citing works
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids
Davis, I., Leaver‐Fay, A., Chen, V. B., Block, J. N., Kapral, G. J., Wang, X., Murray, L. W., Arendall, W. B., Snoeyink, J. S., Richardson, J. S., et al. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm216 · Cited by 3,915 · see citing works
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., Belli, B., Bruncko, M., Deckwerth, T. L., Dinges, J., Hajduk, P. J., et al. (2005) · Nature · doi:10.1038/nature03579 · Cited by 3,407 · see citing works
ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., Johnson, E. F., Marsh, K. C., Mitten, M. J., Nimmer, P., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5836 · Cited by 1,992 · see citing works
Differential Targeting of Prosurvival Bcl-2 Proteins by Their BH3-Only Ligands Allows Complementary Apoptotic Function
Chen, L., Willis, S. N., Wei, A., Smith, B. J., Fletcher, J. I., Hinds, M. G., Colman, P. M., Day, C. L., Adams, J. M., & Huang, D. C. S. (2005) · Molecular Cell · doi:10.1016/j.molcel.2004.12.030 · Cited by 1,816 · see citing works
Involvement of the bcl -2 Gene in Human Follicular Lymphoma
Tsujimoto, Y., Cossman, J., Jaffe, E. S., & Croce, C. M. (1985) · Science · doi:10.1126/science.3874430 · Cited by 1,787 · see citing works
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics
Letai, A., Bassik, M. C., Walensky, L. D., Sorcinelli, M. D., Weiler, S., & Korsmeyer, S. J. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00127-7 · Cited by 1,677 · see citing works
Self-citation
Structure of Bcl-x L -Bak Peptide Complex: Recognition Between Regulators of Apoptosis
Sattler, M., Liang, H., Nettesheim, D., Meadows, R. P., Harlan, J. E., Eberstadt, M., Yoon, H. S., Shuker, S. B., Chang, B. S., Minn, A. J., et al. (1997) · Science · doi:10.1126/science.275.5302.983 · Cited by 1,476 · see citing works
X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death
Muchmore, S. W., Sattler, M., Liang, H., Meadows, R. P., Harlan, J. E., Yoon, H. S., Nettesheim, D. G., Chang, B. S., Thompson, C. B., Wong, S., et al. (1996) · Nature · doi:10.1038/381335a0 · Cited by 1,467 · see citing works
Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix
Walensky, L. D., Kung, A. L., Escher, I., Malia, T. J., Barbuto, S., Wright, R. D., Wagner, G., Verdine, G. L., & Korsmeyer, S. J. (2004) · Science · doi:10.1126/science.1099191 · Cited by 1,349 · see citing works
Self-citation
The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
van Delft, M. F., Wei, A. H., Mason, K. D., Vandenberg, C. J., Chen, L., Czabotar, P. E., Willis, S. N., Scott, C. L., Day, C. L., Cory, S., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.027 · Cited by 1,237 · see citing works
Likelihood-enhanced fast rotation functions
Storoni, L. C., McCoy, A. J., & Read, R. J. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444903028956 · Cited by 1,177 · see citing works
An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides
Schafmeister, C. E., Po, J., & Verdine, G. L. (2000) · Journal of the American Chemical Society · doi:10.1021/ja000563a · Cited by 1,037 · see citing works
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia
Konopleva, M. Y., Contractor, R., Tsao, T., Samudio, I. J., Ruvolo, P. P., Kitada, S., Deng, X., Zhai, D., Shi, Y.-X., Sneed, T. B., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.006 · Cited by 1,020 · see citing works
BAX activation is initiated at a novel interaction site
Gavathiotis, E., Suzuki, M., Davis, M. L., Pitter, K., Bird, G. H., Katz, S. G., Tu, H.-C., Kim, H., Cheng, E. H.-Y., Tjandra, N., et al. (2008) · Nature · doi:10.1038/nature07396 · Cited by 700 · see citing works
Self-citation
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Nguyen, M., Marcellus, R. C., Roulston, A., Watson, M., Serfass, L., Madiraju, S. R. M., Goulet, D., Viallet, J., Bélec, L., Billot, X., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709443104 · Cited by 658 · see citing works
Activity-based probes for the proteomic profiling of metalloproteases
Saghatelian, A., Jessani, N., Joseph, A., Humphrey, M., & Cravatt, B. F. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402784101 · Cited by 456 · see citing works
A Stapled BID BH3 Helix Directly Binds and Activates BAX
Walensky, L. D., Pitter, K., Morash, J., Oh, K. J., Barbuto, S., Fisher, J., Smith, E., Verdine, G. L., & Korsmeyer, S. J. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.08.020 · Cited by 383 · see citing works
Self-citation
Discovery, Characterization, and Structure−Activity Relationships Studies of Proapoptotic Polyphenols Targeting B-Cell Lymphocyte/Leukemia-2 Proteins
Kitada, S., Leone, M., Sareth, S., Zhai, D., Reed, J. C., & Pellecchia, M. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm030190z · Cited by 382 · see citing works
Myeloid cell factor–1 is a critical survival factor for multiple myeloma
Zhang, B., Gojo, I., & Fenton, R. G. (2002) · Blood · doi:10.1182/blood.v99.6.1885 · Cited by 368 · see citing works
Mcl-1 is a potential therapeutic target in multiple types of cancer
Akgül, C. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8637-6 · Cited by 329 · see citing works
Dual role of proapoptotic BAD in insulin secretion and beta cell survival
Danial, N. N., Walensky, L. D., Zhang, C.-Y., Choi, C. S., Fisher, J. K., Molina, A. J. A., Datta, S. R., Pitter, K. L., Bird, G. H., Wikstrom, J. D., et al. (2008) · Nature Medicine · doi:10.1038/nm1717 · Cited by 307 · see citing works
Self-citation
Structure-Based Design of Potent Small-Molecule Inhibitors of Anti-Apoptotic Bcl-2 Proteins
Wang, G., Nikolovska‐Coleska, Z., Yang, C., Wang, R., Tang, G., Guo, J., Shangary, S. K., Qiu, S., Gao, W., Yang, D., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm060460o · Cited by 293 · see citing works
MCL-1S, a Splicing Variant of the Antiapoptotic BCL-2 Family Member MCL-1, Encodes a Proapoptotic Protein Possessing Only the BH3 Domain
Bae, J., Leo, C. P., Hsu, S. Y., & Hsueh, A. J. W. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m909826199 · Cited by 291 · see citing works
Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death.
Ricci, M., Kim, S.-H., Ogi, K., Plastaras, J. P., Ling, J., Wang, W.-G., Jin, Z.-Y., Liu, Y.-Q. Y., Dicker, D., Chiao, P. J., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.006 · Cited by 276 · see citing works
‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737
Lin, X., Morgan-Lappe, S. E., Huang, X., Li, L., Zakula, D., Vernetti, L. A., Fesik, S. W., & Shen, Y. (2006) · Oncogene · doi:10.1038/sj.onc.1210166 · Cited by 245 · see citing works
Ring-Closing Metathesis of Olefinic Peptides: Design, Synthesis, and Structural Characterization of Macrocyclic Helical Peptides
Blackwell, H. E., Sadowsky, J., Howard, R. J., Sampson, J. N., Chao, J. A., Steinmetz, W. E., O’Leary, D. J., & Grubbs, R. H. (2001) · The Journal of Organic Chemistry · doi:10.1021/jo015533k · Cited by 222 · see citing works
Mcl-1 Mediates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance in Human Cholangiocarcinoma Cells
Taniai, M., Grambihler, A., Higuchi, H., Werneburg, N., Bronk, S. F., Farrugia, D. J., Kaufmann, S. H., & Gores, G. J. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2770 · Cited by 218 · see citing works
Structure of the BH3 Domains from the p53-Inducible BH3-Only Proteins Noxa and Puma in Complex with Mcl-1
Day, C. L., Smits, C., Fan, F. C., Lee, E. F., Fairlie, W. D., & Hinds, M. G. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.05.071 · Cited by 204 · see citing works
Myeloid Cell Leukemia-1 Inversely Correlates with Glycogen Synthase Kinase-3β Activity and Associates with Poor Prognosis in Human Breast Cancer
Ding, Q., He, X., Xia, W., Hsu, J.-M., Chen, C., Li, L., Lee, D., Yang, J.-Y., Xie, X., Liu, J.-C., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-1788 · Cited by 195 · see citing works
Unique Biology of Mcl-1: Therapeutic Opportunities in Cancer
Shore, G. C., & Warr, M. R. (2008) · Current Molecular Medicine · doi:10.2174/156652408783769580 · Cited by 193 · see citing works
Mcl-1 Interacts with Truncated Bid and Inhibits Its Induction of Cytochrome c Release and Its Role in Receptor-mediated Apoptosis
Clohessy, J. G., Zhuang, J., de Boer, J., Gil‐Gómez, G., & Brady, H. J. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505688200 · Cited by 184 · see citing works
Interrelated Roles for Mcl-1 and BIM in Regulation of TRAIL-mediated Mitochondrial Apoptosis
Han, J., Goldstein, L. A., Gastman, B., & Rabinowich, H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510349200 · Cited by 181 · see citing works
Differential Regulation of Bax and Bak by Anti-apoptotic Bcl-2 Family Proteins Bcl-B and Mcl-1
Zhai, D., Jin, C., Huang, Z., Satterthwait, A. C., & Reed, J. C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708426200 · Cited by 138 · see citing works
Mcl-1 Is Required for Melanoma Cell Resistance to Anoikis
Boisvert-Adamo, K., Longmate, W. M., Abel, E. V., & Aplin, A. E. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0358 · Cited by 128 · see citing works
Mcl-1: A Gateway to TRAIL Sensitization
Kim, S., Ricci, M., & El‐Deiry, W. S. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6278 · Cited by 114 · see citing works
MCL-1 as a Buffer for Proapoptotic BCL-2 Family Members during TRAIL-induced Apoptosis
Meng, X. W., Lee, S. H., Dai, H., Loegering, D. A., Yu, C., Flatten, K. S., Schneider, P. A., Dai, N. T., Kumar, S. K., Smith, B. D., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706110200 · Cited by 108 · see citing works
Chapter 22 Synthesis and Biophysical Characterization of Stabilized α‐Helices of BCL‐2 Domains
Bird, G. H., Bernal, F., Pitter, K. L., & Walensky, L. D. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)01622-4 · Cited by 95 · see citing works
Self-citation
Hydrophile scanning as a complement to alanine scanning for exploring and manipulating protein–protein recognition: Application to the Bim BH3 domain
Boersma, M., Sadowsky, J., Tomita, Y. A., & Gellman, S. H. (2008) · Protein Science · doi:10.1110/ps.032896.107 · Cited by 75 · see citing works
Chapter 23 Dissection of the BCL‐2 Family Signaling Network with Stabilized α‐Helices of BCL‐2 Domains
Pitter, K. L., Bernal, F., LaBelle, J. L., & Walensky, L. D. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)01623-6 · Cited by 46 · see citing works
Self-citation
Structure of (±)-(1R*,4S*,6S*)-1-benzyloxy-4,8,11,11-tetramethyl-6-phenylthiobicyclo[5.3.1]undec-7-en-3-one
Lynch, V. M., Tanaka, T., FISHPAUGH, J. R., et al. (1990) · Acta Crystallographica Section C Crystal Structure Communications · doi:10.1107/s0108270190002104 · Cited by 3 · see citing works

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Scott, D. E., Bayly, A. R., Abell, C., & Skidmore, J. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.29 · Cited by 1,137 · see citing works
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Inhibition of α-helix-mediated protein–protein interactions using designed molecules
Azzarito, V., Long, K., Murphy, N. S., & Wilson, A. J. (2013) · Nature Chemistry · doi:10.1038/nchem.1568 · Cited by 727 · see citing works
Mechanisms of Action of Bcl-2 Family Proteins
Shamas-Din, A., Kale, J., Leber, B., & Andrews, D. W. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008714 · Cited by 705 · see citing works
Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497 · see citing works
Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)
Leverson, J. D., Zhang, H., Chen, J., Tahir, S. K., Phillips, D. C., Xue, J., Nimmer, P., Jin, S., Smith, M., Xiao, Y., et al. (2015) · Cell Death & Disease · doi:10.1038/cddis.2014.561 · Cited by 440 · see citing works
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381 · see citing works
Synthesis of all-hydrocarbon stapled α-helical peptides by ring-closing olefin metathesis
Kim, Y.-W., Grossmann, T. N., & Verdine, G. L. (2011) · Nature Protocols · doi:10.1038/nprot.2011.324 · Cited by 376 · see citing works
Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin
Grossmann, T. N., Yeh, J. T.-H., Bowman, B. R., Chu, Q., Moellering, R. E., & Verdine, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208396109 · Cited by 268 · see citing works
Structure of the Stapled p53 Peptide Bound to Mdm2
Baek, S., Kutchukian, P. S., Verdine, G. L., Huber, R., Holak, T. A., Lee, K. W., & Popowicz, G. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja2090367 · Cited by 259 · see citing works
Design and Structure of Stapled Peptides Binding to Estrogen Receptors
Phillips, C., Roberts, L. R., Schade, M., Bazin, R., Bent, A., Davies, N. L., Moore, R., Pannifer, A. D., Pickford, A. R., Prior, S. H., et al. (2011) · Journal of the American Chemical Society · doi:10.1021/ja202946k · Cited by 247 · see citing works
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Glas, A., Bier, D., Hahne, G., Rademacher, C., Ottmann, C., & Grossmann, T. N. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201310082 · Cited by 145 · see citing works
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Authors: Stewart, M. L., Fire, E., Keating, A. E., & Walensky, L. D.
Affiliations: Boston Children's Hospital (US)
Massachusetts Institute of Technology (US)
Corresponding author: Walensky, Loren D
ORCID: Stewart, Michelle L
Keating, Amy E
Walensky, Loren D
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2010-06-20
Volume: 6
Issue: 8
Pages: 595-601
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.391
PMC: PMC3033224
OpenAlex: W1551855406
Cited by: 418
References: 45
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FWCI: 16.41
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Chemical Biology (publishedVersion)
Worldwide Protein Data Bank (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
PMC
Funders: U.S. Department of Energy (AC02‐06CH11357, 06CH11357, RR-15301, DE-AC02-)
National Institutes of Health (1f31ca144566-01, DE-AC02–06CH11357, 5r01gm084181-04, 5P01CA92625, RR15301)
National Cancer Institute (F31 CA144566, 1F31CA144566, P01CA092625, 5P01CA92625)
National Institute of General Medical Sciences (R01-GM084181, 5R01GM084181)
National Center for Research Resources (RR 15301, P41RR015301)
Basic Energy Sciences (DE-AC02, AC02‐06CH11357, 06CH11357, RR-15301)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: Mcl-1, stapled peptides, Bcl-2 family proteins, Mcl-1 inhibitors, apoptosis sensitization, Bak, binding specificity, chemoresistance, caspase-dependent apoptosis, anti-apoptotic proteins
MeSH terms: Amino Acid Sequence, Cell Survival, Cross-Linking Reagents, Enzyme Activation, Humans, Mitochondria, Models, Molecular, Molecular Sequence Data, Peptides, Protein Binding, Apoptosis, Protein Structure, Secondary, Crystallography, X-Ray, Jurkat Cells, Proto-Oncogene Proteins c-bcl-2, Cytochromes c, Immunoprecipitation, bcl-2 Homologous Antagonist-Killer Protein, Caspase 3, Caspase 7, Myeloid Cell Leukemia Sequence 1 Protein

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The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

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