6IJL

Crystal structure of SmyD3 in complex with covalent inhibitor 5

Summary for 6IJL

• Entry DOI: 10.2210/pdb6ijl/pdb
• Related: 5XXD 5XXG 5XXJ 5YJO
• Descriptor: Histone-lysine N-methyltransferase SMYD3, propyl (2~{R})-4-[2-[4-(1-azanylcyclopropyl)phenyl]quinolin-7-yl]carbonyl-2-methyl-piperazine-1-carboxylate, ZINC ION, ... (5 entities in total)
• Functional Keywords: covalent inhibitor, methyltransferase, methyltransferase inhibitor, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 50245.36

Authors

Baburajendran, N.,Joy, J. (deposition date: 2018-10-10, release date: 2019-08-14, Last modification date: 2024-03-27)

Primary citation

Huang, C.,Liew, S.S.,Lin, G.R.,Poulsen, A.,Ang, M.J.Y.,Chia, B.C.S.,Chew, S.Y.,Kwek, Z.P.,Wee, J.L.K.,Ong, E.H.,Retna, P.,Baburajendran, N.,Li, R.,Yu, W.,Koh-Stenta, X.,Ngo, A.,Manesh, S.,Fulwood, J.,Ke, Z.,Chung, H.H.,Sepramaniam, S.,Chew, X.H.,Dinie, N.,Lee, M.A.,Chew, Y.S.,Low, C.B.,Pendharkar, V.,Manoharan, V.,Vuddagiri, S.,Sangthongpitag, K.,Joy, J.,Matter, A.,Hill, J.,Keller, T.H.,Foo, K.
Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.
Acs Med.Chem.Lett., 10:978-984, 2019

PubMed Abstract: SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

PubMed: 31223458
DOI: 10.1021/acsmedchemlett.9b00170

Experimental method

X-RAY DIFFRACTION (2.351 Å)