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

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 Bradner; Kimberly Stegmaier; Nathanael S Gray

doi:10.1038/s41467-020-18377-w

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.

Authors

Behnam Nabet^#^{1

2}, Fleur M Ferguson^#^{3

4}, Bo Kyung A Seong^{5

6}, Miljan Kuljanin⁷, Alan L Leggett³, Mikaela L Mohardt³, Amanda Robichaud⁵, Amy S Conway⁵, Dennis L Buckley^{8

9}, Joseph D Mancias⁷, 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. behnam_nabet@dfci.harvard.edu.
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. behnam_nabet@dfci.harvard.edu.
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. nathanael_gray@dfci.harvard.edu.
¹³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. nathanael_gray@dfci.harvard.edu.

^# Contributed equally.

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 dTAG^V-1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12^F36V-tagged proteins. dTAG^V-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Female
Gene Knockout Techniques
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Models, Animal
Peptide Hydrolases / metabolism*
Proteins / metabolism*
Proteomics
Proto-Oncogene Proteins p21(ras) / genetics
Tacrolimus Binding Protein 1A / genetics
Tacrolimus Binding Protein 1A / metabolism
Tacrolimus Binding Proteins
Von Hippel-Lindau Tumor Suppressor Protein / genetics
Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

Proteins
Von Hippel-Lindau Tumor Suppressor Protein
Peptide Hydrolases
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)
Tacrolimus Binding Protein 1A
Tacrolimus Binding Proteins
VHL protein, human
VHL protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding