9Q89

Crystal structure of the human METTL3-METTL14 in complex with small molecule inhibitor Compound 13

This is a non-PDB format compatible entry.

Summary for 9Q89

• Entry DOI: 10.2210/pdb9q89/pdb
• Related: 9IH5
• Descriptor: N6-adenosine-methyltransferase catalytic subunit, N(6)-adenosine-methyltransferase non-catalytic subunit METTL14, (3~{R})-~{N}-(cyclopropylmethyl)-1-[6-[3-[4-(6-pyrrolidin-1-ylpyrazin-2-yl)-1,2,3-triazol-1-yl]oxetan-3-yl]pyridin-3-yl]piperidin-3-amine, ... (5 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: 57739.10

Authors

Dutheuil, G.,Oukoloff, K. (deposition date: 2025-02-24, release date: 2026-04-22, Last modification date: 2026-05-06)

Primary citation

Dutheuil, G.,Oukoloff, K.,Lenoir, F.,Korac, J.,El Bousmaqui, M.,Probst, N.,Lapin, A.,Nakhabina, G.,Parmentier, N.,Sorlet, C.,Fraser, G.L.
Optimization of METTL3 Inhibitors for the Treatment of Solid Tumors and AML.
J.Med.Chem., 69:9585-9602, 2026

PubMed Abstract: Further lead optimization of our series of METTL3 inhibitors is disclosed where aggregative replacements of the α-methylpyridone core and 5-dimethylaminopyridin-3-yl-1,2,3-triazole hinge moiety with an oxetan-3-yl-pyridin-3-yl core and 5-cyclopropylpyridin-3-yl-1,3,4-thiadiazol-2-yl hinge moiety, respectively, improved oral bioavailability while decreasing lipophilicity, thereby translating into oral efficacy in mouse tumor models. This research culminates in the discovery of , a compound with a clear selectivity profile and a favorable ADME/PK profile in addition to robust efficacy in AML and solid tumor models. has entered clinical development for the treatment of advanced solid tumors.

PubMed: 41978353
DOI: 10.1021/acs.jmedchem.6c00474

Experimental method

X-RAY DIFFRACTION (1.95 Å)