Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model...

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Transactive response DNA-binding protein of 43 kDa (TDP-43) pathology is central to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Targeting TDP-43 represents a key strategy for disease modification.
• Tau tubulin kinase 1 (TTBK1) is a therapeutic target, but isoform selectivity (over TTBK2) is crucial to prevent ciliogenesis issues.

Purpose of the Study:

• To discover selective and brain-penetrant inhibitors of TTBK1.
• To evaluate the therapeutic potential of these inhibitors in models of FTD-TDP.

Main Methods:

• Structure-guided medicinal chemistry program to identify TTBK1 inhibitors.
• Assessment of compound selectivity, brain penetration, and impact on ciliogenesis.
• Evaluation of TDP-43 phosphorylation in cellular models and FTD patient-derived cells.
• In vivo studies in an FTD-TDP mouse model to assess cognitive function, neuroprotection, and neuroinflammation.

Main Results:

• Discovery of potent and selective TTBK1 inhibitors with central nervous system exposure and no ciliogenesis liabilities.
• Inhibitors effectively reduced TDP-43 phosphorylation in neuroblastoma cells and FTD patient-derived models.
• Optimized lead compound showed good brain penetration (3:1 ratio), a wide therapeutic window, and demonstrated efficacy in vivo.
• In vivo administration improved cognitive deficits, provided neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model.

Conclusions:

• Selective TTBK1 inhibitors are promising therapeutic agents for TDP-43 proteinopathies.
• These compounds offer a potential disease-modifying strategy for FTD and related neurodegenerative disorders.
• The developed inhibitors warrant further investigation for clinical application in treating neurodegenerative diseases.