posted on 2021-05-04, 14:36authored byTamara Halkina, Jaclyn L. Henderson, Edward Y. Lin, Martin K. Himmelbauer, J. Howard Jones, Marta Nevalainen, Jun Feng, Kristopher King, Michael Rooney, Joshua L. Johnson, Douglas J. Marcotte, Jayanth V. Chodaparambil, P. Rajesh Kumar, Thomas A. Patterson, Paramasivam Murugan, Eli Schuman, LaiYee Wong, Thomas Hesson, Sarah Lamore, Channa Bao, Michael Calhoun, Hannah Certo, Brenda Amaral, Gregory M. Dillon, Rab Gilfillan, Felix Gonzalez-Lopez de Turiso
Structural analysis of the known
NIK inhibitor 3 bound
to the kinase domain of TTBK1 led to the design and synthesis of a
novel class of azaindazole TTBK1 inhibitors exemplified by 8 (cell IC50: 571 nM). Systematic optimization of this
series of analogs led to the discovery of 31, a potent
(cell IC50: 315 nM) and selective TTBK inhibitor with suitable
CNS penetration (rat Kp,uu: 0.32) for in vivo proof of
pharmacology studies. The ability of 31 to inhibit tau
phosphorylation at the disease-relevant Ser 422 epitope was demonstrated
in both a mouse hypothermia and a rat developmental model and provided
evidence that modulation of this target may be relevant in the treatment
of Alzheimer’s disease and other tauopathies.