5IU2
Discovery of imidazoquinolines as a novel class of potent, selective and in vivo efficacious COT kinase inhibitors
Summary for 5IU2
| Entry DOI | 10.2210/pdb5iu2/pdb |
| Descriptor | Mitogen-activated protein kinase kinase kinase 8, N-[2-(morpholin-4-yl)ethyl]-6-(8-phenyl-1H-imidazo[4,5-c][1,7]naphthyridin-1-yl)-1,3-benzothiazol-2-amine (3 entities in total) |
| Functional Keywords | cot, tpl-2, map3k8, kinase, inhibitor, complex, transferase |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm : P41279 |
| Total number of polymer chains | 2 |
| Total formula weight | 76285.62 |
| Authors | Gutmann, S.,Hinniger, A. (deposition date: 2016-03-17, release date: 2016-08-24, Last modification date: 2025-01-29) |
| Primary citation | Glatthar, R.,Stojanovic, A.,Troxler, T.,Mattes, H.,Mobitz, H.,Beerli, R.,Blanz, J.,Gassmann, E.,Druckes, P.,Fendrich, G.,Gutmann, S.,Martiny-Baron, G.,Spence, F.,Hornfeld, J.,Peel, J.E.,Sparrer, H. Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors. J.Med.Chem., 59:7544-7560, 2016 Cited by PubMed Abstract: Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases. PubMed: 27502541DOI: 10.1021/acs.jmedchem.6b00598 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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