Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer.
• VHL tumor suppressor inactivation is common in ccRCC, creating therapeutic vulnerabilities.
• HIF2α inhibitors show promise but resistance is an issue, highlighting the need for new targets like TBK1.

Purpose of the Study:

• To develop and characterize a novel proteolysis-targeting chimera (PROTAC) for TBK1 degradation.
• To evaluate the efficacy and selectivity of the PROTAC UNC8209 in VHL-deficient ccRCC models.
• To explore the therapeutic potential of TBK1 degradation in various cancer types.

Main Methods:

• Development of UNC8209, a cereblon (CRBN)-recruiting PROTAC targeting TBK1.
• Assessment of TBK1 degradation efficiency and kinase selectivity compared to existing degraders.
• In vitro proliferation assays in VHL-deficient ccRCC models.
• In vivo tumor growth studies and toxicity assessments.

Main Results:

• UNC8209 selectively and potently degrades TBK1.
• UNC8209 demonstrates enhanced degradation efficiency and selectivity over off-target kinases like IKKε.
• TBK1 degradation by UNC8209 suppresses proliferation in ccRCC models and reduces tumor growth in vivo with minimal toxicity.
• Anti-proliferative effects were observed in other tumor types dependent on elevated TBK1 activity.

Conclusions:

• UNC8209 is a selective chemical probe for TBK1 degradation.
• TBK1 degradation represents a viable therapeutic strategy for TBK1-dependent cancers, including ccRCC.
• UNC8209 shows potential for treating various cancers with specific molecular dependencies.