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

  • Nat Commun. 2020 Sep 18;11(1):4687. doi: 10.1038/s41467-020-18377-w.
Behnam Nabet   #  1  2 ,  Fleur M Ferguson   #  3  4 ,  Bo Kyung A Seong  5  6 ,  Miljan Kuljanin  7 ,  Alan L Leggett  3 ,  Mikaela L Mohardt  3 ,  Amanda Robichaud  5 ,  Amy S Conway  5 ,  Dennis L Buckley  8  9 ,  Joseph D Mancias  7 ,  James E Bradner  8  10  9 ,  Kimberly Stegmaier  5  6  11 ,  Nathanael S Gray  12  13
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 5. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6. The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 7. Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 9. Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 10. Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 11. Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
  • 12. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 13. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 32948771 DOI: 10.1038/s41467-020-18377-w
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.

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