ccRCC cells treated with DMSO or UNC8209

Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, often features inactivation of the VHL tumor suppressor, creating therapeutic vulnerabilities. Although HIF2α inhibitors have shown promise, many VHL-deficient tumors remain resistant. TANK-binding kinase 1 (TBK1) has been identified as a synthetic lethal target in this context. Here, we describe the development of UNC8209, an optimized cereblon-based recruiting Proteolysis-targeting chimeras (PROTACs) that selectively and potently degrades TBK1. Compared to earlier compounds, UNC8209 exhibits enhanced degradation efficiency, improved selectivity over off-target kinases such as IKKε, and robust anti-proliferative activity in VHL-deficient RCC models. Sensitivity to UNC8209 correlates with TBK1 activity in general across cell lines. We also generated a negative control compound that confirms target-specific effects. In addition, UNC8209 effectively suppresses tumor growth in vivo with minimal toxicity, supporting its therapeutic potential as a next-generation TBK1-targeting strategy for VHL-deficient cancers.