6SFC

EED in complex with a methyl-thiazole

Summary for 6SFC

• Entry DOI: 10.2210/pdb6sfc/pdb
• Descriptor: Polycomb protein EED, CALCIUM ION, N-(2,3-dihydro-1-benzofuran-4-ylmethyl)-8-(4-methylsulfonylphenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine, ... (5 entities in total)
• Functional Keywords: methyltransferase eed prc2 epigenetic h3k27 wd40 inhibitor, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 85428.41

Authors

Read, J.A. (deposition date: 2019-08-01, release date: 2019-09-25, Last modification date: 2024-05-15)

Primary citation

Read, J.A.,Tart, J.,Rawlins, P.B.,Gregson, C.,Jones, K.,Gao, N.,Zhu, X.,Tomlinson, R.,Code, E.,Cheung, T.,Chen, H.,Kawatkar, S.P.,Bloecher, A.,Bagal, S.,O'Donovan, D.H.,Robinson, J.
Rapid Identification of Novel Allosteric PRC2 Inhibitors.
Acs Chem.Biol., 14:2134-2140, 2019

PubMed Abstract: Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates chromatin state and gene expression by methylating histone H3 lysine 27. EZH2 is overexpressed or mutated in various hematological malignancies and solid cancers. Our previous efforts to identify inhibitors of PRC2 methyltransferase activity by high-throughput screening (HTS) resulted in large numbers of false positives and thus a significant hit deconvolution challenge. More recently, others have reported compounds that bind to another PRC2 core subunit, EED, and allosterically inhibit EZH2 activity. This mechanism is particularly appealing as it appears to retain potency in cell lines that have acquired resistance to orthosteric EZH2 inhibition. By designing a fluorescence polarization probe based on the reported EED binding compounds, we were able to quickly and cleanly re-triage our previously challenging HTS hit list and identify novel allosteric PRC2 inhibitors.

PubMed: 31525019
DOI: 10.1021/acschembio.9b00468

Experimental method

X-RAY DIFFRACTION (2 Å)