학술논문
Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo
Document Type
Article
Author
Halkina, Tamara; Henderson, Jaclyn L.; Lin, Edward Y.; Himmelbauer, Martin K.; Jones, J. Howard; Nevalainen, Marta; Feng, Jun; King, Kristopher; Rooney, Michael; Johnson, Joshua L.; Marcotte, Douglas J.; Chodaparambil, Jayanth V.; Kumar, P. Rajesh; Patterson, Thomas A.; Murugan, Paramasivam; Schuman, Eli; Wong, LaiYee; Hesson, Thomas; Lamore, Sarah; Bao, Channa; Calhoun, Michael; Certo, Hannah; Amaral, Brenda; Dillon, Gregory M.; Gilfillan, Rab; de Turiso, Felix Gonzalez-Lopez
Source
Journal of Medicinal Chemistry; 20210101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
Structural analysis of the known NIK inhibitor 3bound 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 31to 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.