Degrading TBK1 to disarm VHL-deficient renal cancer

Hyunwoo Kwon; Alan E Bers; David A Barbie

doi:10.1016/j.chembiol.2026.03.015

Degrading TBK1 to disarm VHL-deficient renal cancer

Cell Chem Biol. 2026 Apr 16;33(4):425-427. doi: 10.1016/j.chembiol.2026.03.015.

Authors

Hyunwoo Kwon¹, Alan E Bers², David A Barbie³

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Parker Institute for Immunotherapy at the Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: david_barbie@dfci.harvard.edu.

PMID: 41997114
DOI: 10.1016/j.chembiol.2026.03.015

Abstract

Clear cell renal cell carcinoma (ccRCC) with von Hippel-Lindau (VHL) loss exhibits TBK1 dependency, and targeted therapeutic strategies outside of HIF-2α inhibition have remained limited. In this issue of Cell Chemical Biology, Liao et al.¹ describe a second-generation cereblon-recruiting TBK1 proteolytic targeting chimera (PROTAC) with promising pre-clinical activity.

MeSH terms

Adaptor Proteins, Signal Transducing
Carcinoma, Renal Cell* / drug therapy
Carcinoma, Renal Cell* / metabolism
Carcinoma, Renal Cell* / pathology
Humans
Kidney Neoplasms* / drug therapy
Kidney Neoplasms* / metabolism
Kidney Neoplasms* / pathology
Protein Serine-Threonine Kinases* / antagonists & inhibitors
Protein Serine-Threonine Kinases* / metabolism
Proteolysis
Ubiquitin-Protein Ligases
Von Hippel-Lindau Tumor Suppressor Protein* / genetics
Von Hippel-Lindau Tumor Suppressor Protein* / metabolism

Substances

Von Hippel-Lindau Tumor Suppressor Protein
Protein Serine-Threonine Kinases
TBK1 protein, human
VHL protein, human
CRBN protein, human
Ubiquitin-Protein Ligases
Adaptor Proteins, Signal Transducing