2. Academic Validation
  3. Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo

Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo

  • J Med Chem. 2021 May 13;64(9):6358-6380. doi: 10.1021/acs.jmedchem.1c00382.
Tamara Halkina 1,  Jaclyn L Henderson 1,  Edward Y Lin 1,  Martin K Himmelbauer 1,  J Howard Jones 1,  Marta Nevalainen 1,  Jun Feng 1,  Kristopher King 2,  Michael Rooney 2,  Joshua L Johnson 2,  Douglas J Marcotte 3,  Jayanth V Chodaparambil 3,  P Rajesh Kumar 3,  Thomas A Patterson 3,  Paramasivam Murugan 4,  Eli Schuman 4,  LaiYee Wong 4,  Thomas Hesson 4,  Sarah Lamore 5,  Channa Bao 6,  Michael Calhoun 6,  Hannah Certo 6,  Brenda Amaral 6,  Gregory M Dillon 6,  Rab Gilfillan 1,  Felix Gonzalez-Lopez de Turiso 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 2 Department of Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 3 Department of Physical Biochemistry and Molecular Design, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 4 Department of Bioassays, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 5 Department of Preclinical Safety, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 6 Department of Emerging Neurosciences Research Unit, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
PMID: 33944571 DOI: 10.1021/acs.jmedchem.1c00382
Abstract

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.

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