6TCU
Glycogen synthase kinase-3 beta (GSK3b) in complex with ligand 1
Summary for 6TCU
| Entry DOI | 10.2210/pdb6tcu/pdb |
| Descriptor | Glycogen synthase kinase-3 beta, 5-[2,3-bis(fluoranyl)phenyl]-~{N}-[[1-(2-methoxyethyl)piperidin-4-yl]methyl]-1~{H}-indazole-3-carboxamide, ACETATE ION, ... (4 entities in total) |
| Functional Keywords | gsk3beta kinase, transferase, inhibitor, proteros |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40887.87 |
| Authors | Lammens, A.,Krapp, S.,Buonfiglio, R.,Ombrato, R. (deposition date: 2019-11-06, release date: 2020-09-16, Last modification date: 2024-10-23) |
| Primary citation | Prati, F.,Buonfiglio, R.,Furlotti, G.,Cavarischia, C.,Mangano, G.,Picollo, R.,Oggianu, L.,di Matteo, A.,Olivieri, S.,Bovi, G.,Porceddu, P.F.,Reggiani, A.,Garrone, B.,Di Giorgio, F.P.,Ombrato, R. Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue andIn VivoActivity in a Mood Disorder Model. Acs Med.Chem.Lett., 11:825-831, 2020 Cited by PubMed Abstract: Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3β (GSK-3β) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3β inhibitors with good efficacy and safety profile associated with high brain exposure is required. Accordingly, we have previously reported the selective indazole-based GSK-3 inhibitor , which showed excellent efficacy in a mouse model of mania. Despite the favorable preclinical profile, analog suffered from activity at the hERG ion channel, which prevented its further progression. Herein, we describe our strategy to improve this off-target liability through modulation of physicochemical properties, such as lipophilicity and basicity. These efforts led to the potent inhibitor , which possessed reduced hERG affinity, promising ADME properties, and was very effective in a mood stabilizer model. PubMed: 32435391DOI: 10.1021/acsmedchemlett.9b00633 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.14 Å) |
Structure validation
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