Hyperphosphorylated tau is the primary component of neurofibrillary tangles, a hallmark pathology associated with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Tau tubulin kinase 1 (TTBK1) is a CNS-specific enzyme that phosphorylates tau at pathologically relevant sites. Several studies have linked TTBK1 activity with neurodegenerative disease, and it has been proposed that inhibition of TTBK1 with an ATP-competitive small molecule might be a viable therapeutic approach for the treatment of AD and other tauopathies.<br/><br/>The starting point of our structure-based design optimization approach was a known NIK inhibitor, which was reported to have activity against TTBK1. Structural analysis of an in-house crystal structure of this compound bound to the kinase domain of TTBK1 led to the discovery of<br/>a novel series of azaindole and azaindazole TTBK1 inhibitors. Optimization of the potency, kinome selectivity, and ADMET properties of our initial hits led to the identification of several tool compounds with a suitable profile for in vivo proof of pharmacology experiments. Acute<br/>treatment with these compounds resulted in a dose-dependent decrease of tau phosphorylation at pathologically relevant sites in mice. A correlation between target engagement and inhibition of tau phosphorylation using a chemoproteomics platform was also established and will be discussed.

Discovery of potent TTBK1 inhibitors that lower tau phosphorylation in vivo for the treatment of Alzheimer’s disease

ACS Spring 2022

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