5H25

EED in complex with PRC2 allosteric inhibitor compound 11

Summary for 5H25

• Entry DOI: 10.2210/pdb5h25/pdb
• Related: 5H13 5H14 5H15 5H17 5H19 5H24
• Descriptor: Polycomb protein EED, Histone-lysine N-methyltransferase EZH2, 5-(2-fluorophenyl)-2,3-dihydroimidazo[2,1-a]isoquinoline, ... (4 entities in total)
• Functional Keywords: eed, prc2, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: O75530 Q15910
• Total number of polymer chains: 4
• Total formula weight: 92485.41

Authors

Zhao, K.,Zhao, M.,Luo, X.,Zhang, H. (deposition date: 2016-10-14, release date: 2017-01-25, Last modification date: 2024-10-23)

Primary citation

Huang, Y.,Zhang, J.,Yu, Z.,Zhang, H.,Wang, Y.,Lingel, A.,Qi, W.,Gu, J.,Zhao, K.,Shultz, M.D.,Wang, L.,Fu, X.,Sun, Y.,Zhang, Q.,Jiang, X.,Zhang, J.,Zhang, C.,Li, L.,Zeng, J.,Feng, L.,Zhang, C.,Liu, Y.,Zhang, M.,Zhang, L.,Zhao, M.,Gao, Z.,Liu, X.,Fang, D.,Guo, H.,Mi, Y.,Gabriel, T.,Dillon, M.P.,Atadja, P.,Oyang, C.
Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy
J. Med. Chem., 60:2215-2226, 2017

PubMed Abstract: Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2 preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.

PubMed: 28092155
DOI: 10.1021/acs.jmedchem.6b01576

Experimental method

X-RAY DIFFRACTION (2.88 Å)