Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression.

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.