6W7F
Structure of EED bound to inhibitor 5285
Summary for 6W7F
| Entry DOI | 10.2210/pdb6w7f/pdb |
| Descriptor | Polycomb protein EED, 8-(6-cyclopropylpyridin-3-yl)-N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | inhibitor, gene regulation, transcription-inhibitor complex |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43463.33 |
| Authors | Petrunak, E.M.,Stuckey, J.A. (deposition date: 2020-03-19, release date: 2020-07-08, Last modification date: 2023-10-18) |
| Primary citation | Rej, R.K.,Wang, C.,Lu, J.,Wang, M.,Petrunak, E.,Zawacki, K.P.,McEachern, D.,Fernandez-Salas, E.,Yang, C.Y.,Wang, L.,Li, R.,Chinnaswamy, K.,Wen, B.,Sun, D.,Stuckey, J.,Zhou, Y.,Chen, J.,Tang, G.,Wang, S. EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development. J.Med.Chem., 63:7252-7267, 2020 Cited by PubMed Abstract: Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC value of 0.2 nM and inhibits cell growth with IC values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date. PubMed: 32580550DOI: 10.1021/acs.jmedchem.0c00479 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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