Development of Potent and Cell Active 5-Azaindole-Based Tau Tubulin Kinase Inhibitors.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Cell Biology

Background:

• Tau tubulin kinase 1 and 2 (TTBK1/2) are implicated in neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal lobe dementia (FTD), and amyotrophic lateral sclerosis (ALS).
• TTBK1/2 substrates include TDP-43, tau, and tubulin, making them potential therapeutic targets.
• TTBK2 plays a role in ciliogenesis, the formation of primary cilia, which are important cellular structures.

Purpose of the Study:

• To develop and characterize potent and selective chemical tools for inhibiting TTBK1 and TTBK2.
• To facilitate the investigation of TTBK1/2-mediated pathways in disease and cellular processes.
• To provide pharmacological probes for studying the role of TTBK1/2 in neurodegeneration and ciliogenesis.

Main Methods:

• Medicinal chemistry campaign to design and synthesize novel kinase inhibitors.
• Biochemical and cellular assays to characterize inhibitor potency and selectivity.
• In-cell assays to assess target engagement and kinome-wide selectivity.

Main Results:

• Development of compound 13, a potent and cell-active inhibitor of both TTBK1 and TTBK2.
• Compound 13 exhibits kinome-wide selectivity.
• Identification of compound 5, a structurally similar negative control lacking in-cell activity against TTBK1/2.

Conclusions:

• Compound 13 serves as a valuable chemical tool for studying TTBK1/2 functions.
• The developed inhibitor can aid research into the therapeutic potential of TTBK1/2 inhibition for neurodegenerative diseases.
• These selective inhibitors facilitate the exploration of TTBK1/2 roles in ciliogenesis and other cellular pathways.