6CJE
Crystal Structure of Mnk2-D228G in complex with Inhibitor
Summary for 6CJE
| Entry DOI | 10.2210/pdb6cje/pdb |
| Related | 6cj5 |
| Descriptor | MAP kinase-interacting serine/threonine-protein kinase 2, ZINC ION, 4-[(9H-purin-6-yl)amino]benzamide, ... (4 entities in total) |
| Functional Keywords | transferase-transferase inhibitor complex, mnk1 inhibitor, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Isoform 2: Nucleus, PML body. Isoform 1: Cytoplasm: Q9HBH9 |
| Total number of polymer chains | 1 |
| Total formula weight | 35924.12 |
| Authors | |
| Primary citation | Reich, S.H.,Sprengeler, P.A.,Chiang, G.G.,Appleman, J.R.,Chen, J.,Clarine, J.,Eam, B.,Ernst, J.T.,Han, Q.,Goel, V.K.,Han, E.Z.R.,Huang, V.,Hung, I.N.J.,Jemison, A.,Jessen, K.A.,Molter, J.,Murphy, D.,Neal, M.,Parker, G.S.,Shaghafi, M.,Sperry, S.,Staunton, J.,Stumpf, C.R.,Thompson, P.A.,Tran, C.,Webber, S.E.,Wegerski, C.J.,Zheng, H.,Webster, K.R. Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. J. Med. Chem., 61:3516-3540, 2018 Cited by PubMed Abstract: Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically. PubMed: 29526098DOI: 10.1021/acs.jmedchem.7b01795 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.36 Å) |
Structure validation
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