2. Academic Validation
  3. Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery

Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery

  • J Med Chem. 2019 Nov 14;62(21):9600-9617. doi: 10.1021/acs.jmedchem.9b01030.
Vadim Bernard-Gauthier 1 2 3,  Andrew V Mossine 4,  Ashley Knight 1 2 5,  Debasis Patnaik 6,  Wen-Ning Zhao 6,  Chialin Cheng 6,  Hema S Krishnan 3,  Lucius L Xuan 6,  Peter S Chindavong 6,  Surya A Reis 6,  Jinshan Michael Chen 7,  Xia Shao 4,  Jenelle Stauff 4,  Janna Arteaga 4,  Phillip Sherman 4,  Nicolas Salem 8,  David Bonsall 9,  Brenda Amaral 8,  Cassis Varlow 1,  Lisa Wells 9,  Laurent Martarello 8,  Shil Patel 5,  Steven H Liang 3,  Ravi G Kurumbail 7,  Stephen J Haggarty 6,  Peter J H Scott 4 10,  Neil Vasdev 1 2 3
Affiliations

Affiliations

  • 1 Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre , Centre for Addiction and Mental Health , Toronto , Ontario M5T 1R8 , Canada.
  • 2 Department of Psychiatry/Institute of Medical Science , University of Toronto , Toronto , Ontario M5T 1R8 , Canada.
  • 3 Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology , Harvard Medical School , Boston , Massachusetts 02114 , United States.
  • 4 Division of Nuclear Medicine, Department of Radiology , The University of Michigan Medical School , Ann Arbor , Michigan 48109 , United States.
  • 5 Eisai AiM Institute , Boston , Massachusetts 01810 , United States.
  • 6 Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry , Harvard Medical School , Boston , Massachusetts 02114 , United States.
  • 7 Pfizer Worldwide Research and Development , Groton Laboratories , Eastern Point Road , Groton , Connecticut 06340 , United States.
  • 8 Biogen, Research and Early Development Imaging , Cambridge , Massachusetts 02142 , United States.
  • 9 Invicro , London W12 0NN , U.K.
  • 10 The Interdepartmental Program in Medicinal Chemistry , University of Michigan , Ann Arbor , Michigan 48109 , United States.
PMID: 31535859 DOI: 10.1021/acs.jmedchem.9b01030
Abstract

Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [3H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β Inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against Wnt/β-catenin signaling activation, was observed in cells.

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