7PUE
Human serum and glucocorticoid-regulated kinase 1 in complex with pyrazolopyridine inhibitor 3a
Summary for 7PUE
| Entry DOI | 10.2210/pdb7pue/pdb |
| Descriptor | Serine/threonine-protein kinase Sgk1, GLYCEROL, 6-[4-[[2,3-bis(chloranyl)phenyl]sulfonylamino]phenyl]-~{N}-[(3~{R})-pyrrolidin-3-yl]-2~{H}-pyrazolo[3,4-b]pyridine-4-carboxamide, ... (4 entities in total) |
| Functional Keywords | serine/threonine protein kinase, atp-competitive inhibitor, dfg-loop, hinge-binder, osteoarthritis, cartilage degradation, pyrazolo-pyridine, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43227.09 |
| Authors | Dreyer, M.K.,Halland, N.,Nazare, M. (deposition date: 2021-09-29, release date: 2021-12-01, Last modification date: 2024-05-01) |
| Primary citation | Halland, N.,Schmidt, F.,Weiss, T.,Li, Z.,Czech, J.,Saas, J.,Ding-Pfennigdorff, D.,Dreyer, M.K.,Strubing, C.,Nazare, M. Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis. J.Med.Chem., 65:1567-1584, 2022 Cited by PubMed Abstract: The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today, no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic, and safety profile. We describe the identification of a highly selective druglike 1-pyrazolo[3,4-]pyrimidine SGK1 inhibitor that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 co-crystal structure, and multiple ligand-based computer models were applied to guide the chemical optimization of the compound ADMET and selectivity profiles. Compounds were selected for subchronic proof of mechanism studies in the mouse femoral head cartilage explant model, and compound emerged as a druglike SGK1 inhibitor, with a highly optimized profile suitable for oral dosing as a novel, potentially disease-modifying agent for osteoarthritis. PubMed: 34931844DOI: 10.1021/acs.jmedchem.1c01601 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.506 Å) |
Structure validation
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