Abstract B027: UNC8209: A potent and selective TBK1 degrader for ccRCC

Abstract 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-recruiting Proteolysis-targeting chimera (PROTAC) 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. Citation Format: Chengheng Liao, Siying Lyu, Rebecca L. Johnson, Xiaoyu Wang, Noelle S. Williams, Lindsey I. James, Lianxin Hu, Qing Zhang. UNC8209: A potent and selective TBK1 degrader for ccRCC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B027.