More than 2 million American adults, or about 1 percent of the population age 18 and older in any given year, have bipolar disorder. Current treatments include the so-called """"""""mood stabilizers,"""""""" lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3b (GSK-3b) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest a potential use of such inhibitors as neuroprotective agents. Neuroprotection may further contribute to the therapeutic efficacy of mood disorder drugs. A number of synthetic GSK-3 inhibitors are now currently available but many of these have not been fully characterized in a battery of biological tests, nor are they readily available to academic researchers. These compounds are largely ATP competitive inhibitors whose kinase activity has been determined in vitro;in many cases their true kinase selectivity profiles and their in vivo action including possible side-effects remain to be established. Clearly, novel, selective and safe GSK-3 inhibitors are needed as both pharmacological tools and as therapeutics for application to a variety of CNS disorders, including various bipolar disorders, but also Parkinson's disease, and Alzheimer's disease to name a few. To date, we have already identified some nM potency GSK-3 inhibitors that emerged from our SAR studies of staurosporine. Moreover, we have found that some of these ligands are able to exert a neuroprotective action in vitro. We anticipate that further research efforts may well lead to compounds that can be advanced to the clinic. To achieve this goal, our aims are as follow:
AIM 1 : Further expand and improve upon the potent GSK-3 inhibitors we have already identified using rational drug design principles;the selection of new ligands for synthesis will be aided by the use of in silico docking methods and these compounds then synthesized in mg to gram amounts;
AIM 2 : All newly synthesized ligands will be tested in the kinase assays to evaluate their selectivity and potency to inhibit the GSK-3 isoforms (both a and b). For the best compounds (Kj values <25 nM), profile them against a limited number of related kinases, namely AKT1/PKBa, CDK2/cyclin E, CDK3/cyclin E, CDK5/p25, and ICK to obtain some measure of kinase selectivity;further characterize selective ligands for in vitro effects by examining their neuroprotective action in cell culture experiments;
AIM 3 : Examine the effects of the best GSK-3 inhibitors (Ki <25 nM with a selectivity of at least 10-fold against other kinases and showing a neuroprotective action in the low micromolar range) for their ability to exert both an antidepressant action as well as anti-manic effects in animal models;
this aim will be carried out by our behavioral collaborators at PsychoGenics Inc. using their patented SmartCube technology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079400-05
Application #
8010220
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (91))
Program Officer
Winsky, Lois M
Project Start
2006-12-18
Project End
2013-11-30
Budget Start
2010-12-30
Budget End
2013-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$440,898
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Pal, Krishnendu; Cao, Ying; Gaisina, Irina N et al. (2014) Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer. Mol Cancer Ther 13:285-96
Gunosewoyo, Hendra; Midzak, Andrew; Gaisina, Irina N et al. (2013) Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis. J Med Chem 56:5115-29
Chen, Po C; Gaisina, Irina N; El-Khodor, Bassem F et al. (2012) Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, that Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy. ACS Chem Neurosci 3:5-11
Kozikowski, Alan P; Gunosewoyo, Hendra; Guo, Songpo et al. (2011) Identification of a glycogen synthase kinase-3β inhibitor that attenuates hyperactivity in CLOCK mutant mice. ChemMedChem 6:1593-602
Chen, Wenwen; Gaisina, Irina N; Gunosewoyo, Hendra et al. (2011) Structure-guided design of a highly selective glycogen synthase kinase-3β inhibitor: a superior neuroprotective pyrazolone showing antimania effects. ChemMedChem 6:1587-92
Gaisina, Irina N; Gallier, Franck; Ougolkov, Andrei V et al. (2009) From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3beta inhibitors that suppress proliferation and survival of pancreatic cancer cells. J Med Chem 52:1853-63
Kim, Ki Hwan; Gaisina, Irina; Gallier, Franck et al. (2009) Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. J Mol Model 15:1463-79