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
  • 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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