4YND

The Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

Summary for 4YND

• Entry DOI: 10.2210/pdb4ynd/pdb
• Descriptor: N-lysine methyltransferase SMYD2, ZINC ION, N-cyclohexyl-N~3~-[2-(3,4-dichlorophenyl)ethyl]-N-(2-{[(2R)-2-hydroxy-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide, ... (5 entities in total)
• Functional Keywords: epigenetics, smyd2, h3k36, p53, methyltransferase, lysine, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : Q9NRG4
• Total number of polymer chains: 1
• Total formula weight: 54378.00

Authors

Sweis, R.F.,Wang, Z.,Algire, M.,Arrowsmith, C.H.,Brown, P.J.,Chiang, G.C.,Guo, J.,Jakob, C.G.,Kennedy, S.,Li, F.,Soni, N.B.,Vedadi, M.,Pappano, W.N. (deposition date: 2015-03-09, release date: 2015-05-20, Last modification date: 2023-09-27)

Primary citation

Sweis, R.F.,Wang, Z.,Algire, M.,Arrowsmith, C.H.,Brown, P.J.,Chiang, G.G.,Guo, J.,Jakob, C.G.,Kennedy, S.,Li, F.,Maag, D.,Shaw, B.,Soni, N.B.,Vedadi, M.,Pappano, W.N.
Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2.
Acs Med.Chem.Lett., 6:695-700, 2015

PubMed Abstract: A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

PubMed: 26101576
DOI: 10.1021/acsmedchemlett.5b00124

Experimental method

X-RAY DIFFRACTION (2.79 Å)