6kg2 | pdb_00006kg2

Human MTHFD2 in complex with Compound 18

spinqualitylabelsall models 6kg2, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6kg2 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: D8C, NAD, PO4 Gene: MTHFD2, NMDMC (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration. Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with In Vivo Anti-Tumor Activity.,Kawai J, Toki T, Ota M, Inoue H, Takata Y, Asahi T, Suzuki M, Shimada T, Ono K, Suzuki K, Takaishi S, Ohki H, Matsui S, Tsutsumi S, Hirota Y, Nakayama K J Med Chem. 2019 Oct 22. doi: 10.1021/acs.jmedchem.9b01113. PMID:31638799 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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