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

• Published in: Journal of medicinal chemistry 2019-11, Vol.62 (21), p.9600-9617
• Main Authors: Bernard-Gauthier, Vadim, Mossine, Andrew V, Knight, Ashley, Patnaik, Debasis, Zhao, Wen-Ning, Cheng, Chialin, Krishnan, Hema S, Xuan, Lucius L, Chindavong, Peter S, Reis, Surya A, Chen, Jinshan Michael, Shao, Xia, Stauff, Jenelle, Arteaga, Janna, Sherman, Phillip, Salem, Nicolas, Bonsall, David, Amaral, Brenda, Varlow, Cassis, Wells, Lisa, Martarello, Laurent, Patel, Shil, Liang, Steven H, Kurumbail, Ravi G, Haggarty, Stephen J, Scott, Peter J. H, Vasdev, Neil
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier - metabolism; Brain - diagnostic imaging; Brain - metabolism; Catalytic Domain; Drug Discovery; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - chemistry; HEK293 Cells; Humans; Mice; Models, Molecular; Neuroimaging; Oxazoles - chemistry; Oxazoles - metabolism; Oxazoles - pharmacology; Positron-Emission Tomography - methods; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Triazoles - chemistry; Triazoles - metabolism; Triazoles - pharmacology
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01030

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.