3OS3
Mitogen-activated protein kinase kinase 1 (MEK1) in complex with CH4858061 and MgATP
Summary for 3OS3
| Entry DOI | 10.2210/pdb3os3/pdb |
| Related | 3ORN |
| Descriptor | Dual specificity mitogen-activated protein kinase kinase 1, ADENOSINE-5'-TRIPHOSPHATE, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)-5-{[(2-hydroxyethoxy)imino]methyl}benzamide, ... (5 entities in total) |
| Functional Keywords | kinase, kinase inhibitor, allosteric, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens More |
| Cellular location | Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : Q02750 |
| Total number of polymer chains | 1 |
| Total formula weight | 35208.29 |
| Authors | Lukacs, C.M.,Janson, C.,Schuck, V.,Belunis, C. (deposition date: 2010-09-08, release date: 2011-07-27, Last modification date: 2024-02-21) |
| Primary citation | Isshiki, Y.,Kohchi, Y.,Iikura, H.,Matsubara, Y.,Asoh, K.,Murata, T.,Kohchi, M.,Mizuguchi, E.,Tsujii, S.,Hattori, K.,Miura, T.,Yoshimura, Y.,Aida, S.,Miwa, M.,Saitoh, R.,Murao, N.,Okabe, H.,Belunis, C.,Janson, C.,Lukacs, C.,Schuck, V.,Shimma, N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg.Med.Chem.Lett., 21:1795-1801, 2011 Cited by PubMed Abstract: The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study. PubMed: 21316218DOI: 10.1016/j.bmcl.2011.01.062 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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