9G4S
Crystal structure of the human METTL3-METTL14 in complex with small molecule inhibitor Compound 56
This is a non-PDB format compatible entry.
Summary for 9G4S
| Entry DOI | 10.2210/pdb9g4s/pdb |
| Descriptor | N6-adenosine-methyltransferase catalytic subunit, N6-adenosine-methyltransferase non-catalytic subunit, 4-[(3~{R})-3-(cyclopropylmethylamino)piperidin-1-yl]-1-[(1~{R})-1-[4-[5-(dimethylamino)pyridin-3-yl]-1,2,3-triazol-1-yl]ethyl]pyridin-2-one, ... (6 entities in total) |
| Functional Keywords | mettl3 mettl14 inhibitor epics, rna binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 57975.44 |
| Authors | Dutheuil, G.,Oukoloff, K. (deposition date: 2024-07-16, release date: 2025-02-12, Last modification date: 2025-08-27) |
| Primary citation | Dutheuil, G.,Oukoloff, K.,Korac, J.,Lenoir, F.,El Bousmaqui, M.,Probst, N.,Lapin, A.,Nakhabina, G.,Sorlet, C.,Parmentier, N.,Karila, D.,Ghavtadze, N.,Casault, P.,Claridge, S.,Sapmaz, S.,Slater, M.J.,Fraser, G.L. Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models. J.Med.Chem., 68:2981-3003, 2025 Cited by PubMed Abstract: METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-methyladenosine (mA), the most abundant modification to mRNA. The prevalence of mA and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of as an proof-of-concept compound. potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors. PubMed: 39883878DOI: 10.1021/acs.jmedchem.4c02225 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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