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
  • 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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