5A7S

Crystal structure of human JMJD2A in complex with compound 44

Summary for 5A7S

• Entry DOI: 10.2210/pdb5a7s/pdb
• Related: 5A7N 5A7O 5A7P 5A7Q 5A7W 5A80
• Descriptor: LYSINE-SPECIFIC DEMETHYLASE 4A, MANGANESE (II) ION, ZINC ION, ... (7 entities in total)
• Functional Keywords: oxidoreductase, jmjd2a, kdm4a
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus : O75164
• Total number of polymer chains: 2
• Total formula weight: 90525.04

Authors

Nowak, R.,Velupillai, S.,Krojer, T.,Gileadi, C.,Johansson, C.,Korczynska, M.,Le, D.D.,Younger, N.,Gregori-Puigjane, E.,Tumber, A.,Iwasa, E.,Pollock, S.B.,Ortiz Torres, I.,Kopec, J.,Tallant, C.,Froese, S.,von Delft, F.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.,Shoichet, B.K.,Fujimori, D.G.,Oppermann, U. (deposition date: 2015-07-09, release date: 2016-01-13, Last modification date: 2024-01-10)

Primary citation

Korczynska, M.,Le, D.D.,Younger, N.,Gregori-Puigjane, E.,Tumber, A.,Krojer, T.,Velupillai, S.,Gileadi, C.,Nowak, R.P.,Iwasa, E.,Pollock, S.B.,Ortiz Torres, I.,Oppermann, U.,Shoichet, B.K.,Fujimori, D.G.
Docking and Linking of Fragments to Discover Jumonji Histone Demethylase Inhibitors.
J.Med.Chem., 59:1580-, 2016

PubMed Abstract: Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600,000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ∼ 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.

PubMed: 26699912
DOI: 10.1021/ACS.JMEDCHEM.5B01527

Experimental method

X-RAY DIFFRACTION (2.2 Å)