2. Academic Validation
  3. Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression

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

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: lianxin.hu@zju.edu.cn.
  • 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: qing.zhang@utsouthwestern.edu.
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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