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Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules

Author

Listed:
  • Behnam Nabet

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Fleur M. Ferguson

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Bo Kyung A. Seong

    (Dana-Farber Cancer Institute
    The Broad Institute of MIT and Harvard)

  • Miljan Kuljanin

    (Dana-Farber Cancer Institute)

  • Alan L. Leggett

    (Dana-Farber Cancer Institute)

  • Mikaela L. Mohardt

    (Dana-Farber Cancer Institute)

  • Amanda Robichaud

    (Dana-Farber Cancer Institute)

  • Amy S. Conway

    (Dana-Farber Cancer Institute)

  • Dennis L. Buckley

    (Dana-Farber Cancer Institute
    Novartis Institutes for BioMedical Research)

  • Joseph D. Mancias

    (Dana-Farber Cancer Institute)

  • James E. Bradner

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Novartis Institutes for BioMedical Research)

  • Kimberly Stegmaier

    (Dana-Farber Cancer Institute
    The Broad Institute of MIT and Harvard
    Boston Children’s Hospital)

  • Nathanael S. Gray

    (Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity over small molecule inhibitors. We describe dTAGV-1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12F36V-tagged proteins. dTAGV-1 overcomes a limitation of previously reported CRBN-recruiting dTAG molecules to degrade recalcitrant oncogenes, supports combination degrader studies and facilitates investigations of protein function in cells and mice.

Suggested Citation

  • Behnam Nabet & Fleur M. Ferguson & Bo Kyung A. Seong & Miljan Kuljanin & Alan L. Leggett & Mikaela L. Mohardt & Amanda Robichaud & Amy S. Conway & Dennis L. Buckley & Joseph D. Mancias & James E. Brad, 2020. "Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18377-w
    DOI: 10.1038/s41467-020-18377-w
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    Cited by:

    1. Daniel P. Bondeson & Zachary Mullin-Bernstein & Sydney Oliver & Thomas A. Skipper & Thomas C. Atack & Nolan Bick & Meilani Ching & Andrew A. Guirguis & Jason Kwon & Carly Langan & Dylan Millson & Bren, 2022. "Systematic profiling of conditional degron tag technologies for target validation studies," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Varadha Balaji Venkadakrishnan & Adam G. Presser & Richa Singh & Matthew A. Booker & Nicole A. Traphagen & Kenny Weng & Nathaniel C. E. Voss & Navin R. Mahadevan & Kei Mizuno & Loredana Puca & Osasena, 2024. "Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Mahshid Gazorpak & Karina M. Hugentobler & Dominique Paul & Pierre-Luc Germain & Miriam Kretschmer & Iryna Ivanova & Selina Frei & Kei Mathis & Remo Rudolf & Sergio Mompart Barrenechea & Vincent Fisch, 2023. "Harnessing PROTAC technology to combat stress hormone receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    4. Christoph Grohmann & Charlene M. Magtoto & Joel R. Walker & Ngee Kiat Chua & Anna Gabrielyan & Mary Hall & Simon A. Cobbold & Stephen Mieruszynski & Martin Brzozowski & Daniel S. Simpson & Hao Dong & , 2022. "Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Haiyan Gu & Jing Yang & Jiayu Zhang & Ying Song & Yao Zhang & Pengfei Xu & Yuanxiang Zhu & Liangliang Wang & Pengfei Zhang & Lin Li & Dahua Chen & Qinmiao Sun, 2022. "PCBP2 maintains antiviral signaling homeostasis by regulating cGAS enzymatic activity via antagonizing its condensation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Chrysanthi Kagiou & Jose A. Cisneros & Jakob Farnung & Joanna Liwocha & Fabian Offensperger & Kevin Dong & Ka Yang & Gary Tin & Christina S. Horstmann & Matthias Hinterndorfer & Joao A. Paulo & Natali, 2024. "Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Andrew J. Tao & Jiewei Jiang & Gillian E. Gadbois & Pavitra Goyal & Bridget T. Boyle & Elizabeth J. Mumby & Samuel A. Myers & Justin G. English & Fleur M. Ferguson, 2023. "A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    8. Jean M. Etersque & Iris K. Lee & Nitika Sharma & Kexiang Xu & Andrew Ruff & Justin D. Northrup & Swarbhanu Sarkar & Tommy Nguyen & Richard Lauman & George M. Burslem & Mark A. Sellmyer, 2023. "Regulation of eDHFR-tagged proteins with trimethoprim PROTACs," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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