Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression

  • Cell Chem Biol. 2026 Apr 16;33(4):461-473.e7. doi: 10.1016/j.chembiol.2026.03.013.
Chengheng Liao  1 ,  Siying Lyu  1 ,  Rebecca L Johnson  2 ,  Tiantian Shang  3 ,  Xiaoyu Wang  4 ,  Nina Gildor  1 ,  Shina Li  1 ,  Noelle S Williams  4 ,  Lindsey I James  5 ,  Lianxin Hu  6 ,  Qing Zhang  7
Affiliations
  • 1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
  • 3. Department of Urology, Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 6. Department of Urology, Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: [email protected].
  • 7. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected].
PMID: 41950925 DOI: 10.1016/j.chembiol.2026.03.013
Abstract

Clear cell renal cell carcinoma (ccRCC), the most common kidney Cancer subtype, often features the inactivation of the von Hippel-Lindau (VHL) tumor suppressor, creating therapeutic vulnerabilities. Although HIF2α inhibitors have shown clinical promise, many VHL-deficient tumors remain resistant. -binding kinase 1 (TBK1) has emerged as a synthetic lethal target in this context. Here, we report UNC8209, an optimized Cereblon(CRBN)-recruiting proteolysis-targeting chimera (PROTAC) that selectively and potently degrades TBK1. Compared with earlier TBK1 degraders, UNC8209 exhibits enhanced degradation efficiency and improved selectivity over off-target kinases, including IKKε. TBK1 degradation by UNC8209 suppresses proliferation in VHL-deficient ccRCC models and impairs tumor growth in vivo with minimal toxicity within a defined therapeutic window. In addition, the anti-proliferative effects of UNC8209 extend to multiple tumor types addicted to elevated TBK1 activity. Together, these findings establish UNC8209 as a selective chemical probe and support TBK1 degradation as a therapeutic strategy in TBK1-dependent cancers.

Keywords
PROTAC; TBK1; VHL; cancer therapeutics; ccRCC; cereblon; targeted protein degradation.
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