5U5H

Crystal structure of EED in complex with 6-(2-fluoro-5-methoxybenzyl)-1-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine 6-(2-fluoro-5-methoxybenzyl)-1-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine

Summary for 5U5H

• Entry DOI: 10.2210/pdb5u5h/pdb
• Related: 5U5K 5U5T 5U62
• Descriptor: Polycomb protein EED, (6S)-6-[(2-fluoro-5-methoxyphenyl)methyl]-1-(propan-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine, GLYCEROL, ... (4 entities in total)
• Functional Keywords: eed, fragment-based generation, oncology, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O75530
• Total number of polymer chains: 1
• Total formula weight: 42765.74

Authors

Bussiere, D.,Shu, W. (deposition date: 2016-12-06, release date: 2017-01-11, Last modification date: 2024-03-06)

Primary citation

Lingel, A.,Sendzik, M.,Huang, Y.,Shultz, M.D.,Cantwell, J.,Dillon, M.P.,Fu, X.,Fuller, J.,Gabriel, T.,Gu, J.,Jiang, X.,Li, L.,Liang, F.,McKenna, M.,Qi, W.,Rao, W.,Sheng, X.,Shu, W.,Sutton, J.,Taft, B.,Wang, L.,Zeng, J.,Zhang, H.,Zhang, M.,Zhao, K.,Lindvall, M.,Bussiere, D.E.
Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase.
J. Med. Chem., 60:415-427, 2017

PubMed Abstract: PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail.

PubMed: 27992714
DOI: 10.1021/acs.jmedchem.6b01473

Experimental method

X-RAY DIFFRACTION (1.8 Å)