1. Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery
Peter S Chindavong,Janna Arteaga,Debasis Patnaik,Peter J H Scott,Brenda Amaral,Ashley Knight,Jinshan Michael Chen,David Bonsall,Cassis Varlow,Andrew V Mossine,Neil Vasdev,Ravi G Kurumbail,Lucius L Xuan,Stephen J Haggarty,Hema S Krishnan,Surya A Reis,Chialin Cheng,Xia Shao,Steven H Liang,Wen-Ning Zhao,Laurent Martarello,Shil Patel,Jenelle Stauff,Phillip Sherman,Vadim Bernard-Gauthier,Nicolas Salem,Lisa Wells J Med Chem . 2019 Nov 14;62(21):9600-9617. 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 CRMP2T514and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.
2. Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging
Fouad Janat,Edward B Holson,Mark S Plummer,Charlie E Nolan,Georges El Fakhri,Debasis Patnaik,Jeanne S Chang,Joel B Schachter,Jinshan Michael Chen,Marc D Normandin,Kimberly S Para,Ravi G Kurumbail,Neil Vasdev,Florence F Wagner,Patrick Trapa,Veerabahu Shanmugasundaram,James M Cook,Stephen J Haggarty,George C Chang,Edward L Conn,Lori Lopresti-Morrow,Roy Perlis,Bruce A Lefker,Steven H Liang,Christine K Taylor,Lorraine F Lanyon,Karl E G Richter,Nicolas J Guehl,Lu Wang,Bradley E Enerson,Elijahu Livni,Ye Che Angew Chem Int Ed Engl . 2016 Aug 8;55(33):9601-5. doi: 10.1002/anie.201603797.
Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.
