7JXX

Structure of TTBK1 kinase domain in complex with Compound 3

Summary for 7JXX

• Entry DOI: 10.2210/pdb7jxx/pdb
• Descriptor: Tau-tubulin kinase 1, 4-(2-amino-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-11-yl)-2-methylbut-3-yn-2-ol, SODIUM ION, ... (4 entities in total)
• Functional Keywords: tau tubulin binding kinase, kinase, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 38284.94

Authors

Chodaprambil, J.V. (deposition date: 2020-08-28, release date: 2021-05-19, Last modification date: 2023-10-18)

Primary citation

Halkina, T.,Henderson, J.L.,Lin, E.Y.,Himmelbauer, M.K.,Jones, J.H.,Nevalainen, M.,Feng, J.,King, K.,Rooney, M.,Johnson, J.L.,Marcotte, D.J.,Chodaparambil, J.V.,Kumar, P.R.,Patterson, T.A.,Murugan, P.,Schuman, E.,Wong, L.,Hesson, T.,Lamore, S.,Bao, C.,Calhoun, M.,Certo, H.,Amaral, B.,Dillon, G.M.,Gilfillan, R.,de Turiso, F.G.
Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo.
J.Med.Chem., 64:6358-6380, 2021

PubMed Abstract: Structural analysis of the known NIK inhibitor bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by (cell IC: 571 nM). Systematic optimization of this series of analogs led to the discovery of , a potent (cell IC: 315 nM) and selective TTBK inhibitor with suitable CNS penetration (rat K: 0.32) for in vivo proof of pharmacology studies. The ability of 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.

PubMed: 33944571
DOI: 10.1021/acs.jmedchem.1c00382

Experimental method

X-RAY DIFFRACTION (1.56 Å)