6MBP

GLP Methyltransferase with Inhibitor EML741- P3121 Crystal Form

Summary for 6MBP

• Entry DOI: 10.2210/pdb6mbp/pdb
• Descriptor: Histone-lysine N-methyltransferase EHMT1, 2-cyclohexyl-7-methoxy-N-[1-(propan-2-yl)piperidin-4-yl]-8-[3-(pyrrolidin-1-yl)propoxy]-3H-1,4-benzodiazepin-5-amine, ZINC ION, ... (6 entities in total)
• Functional Keywords: histone, h3, methylation inhibition, transferase, transferase-transferase inhbitor complex, transferase/transferase inhbitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63549.16

Authors

Horton, J.R.,Cheng, X. (deposition date: 2018-08-30, release date: 2019-02-27, Last modification date: 2023-10-11)

Primary citation

Milite, C.,Feoli, A.,Horton, J.R.,Rescigno, D.,Cipriano, A.,Pisapia, V.,Viviano, M.,Pepe, G.,Amendola, G.,Novellino, E.,Cosconati, S.,Cheng, X.,Castellano, S.,Sbardella, G.
Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure.
J. Med. Chem., 62:2666-2689, 2019

PubMed Abstract: Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been reported. Herein, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3 H-benzo[ e][1,4]diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood-brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors.

PubMed: 30753076
DOI: 10.1021/acs.jmedchem.8b02008

Experimental method

X-RAY DIFFRACTION (1.947 Å)