7QK4

EED in complex with PRC2 allosteric inhibitor compound 22 (MAK683)

Summary for 7QK4

• Entry DOI: 10.2210/pdb7qk4/pdb
• Related: 7QJG 7QJU
• Descriptor: Polycomb protein EED, Histone-lysine N-methyltransferase EZH2, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 46331.98

Authors

Zhao, K.,Zhao, M.,Luo, X.,Zhang, H.,Scheufler, C. (deposition date: 2021-12-17, release date: 2022-04-13, Last modification date: 2024-01-31)

Primary citation

Huang, Y.,Sendzik, M.,Zhang, J.,Gao, Z.,Sun, Y.,Wang, L.,Gu, J.,Zhao, K.,Yu, Z.,Zhang, L.,Zhang, Q.,Blanz, J.,Chen, Z.,Dubost, V.,Fang, D.,Feng, L.,Fu, X.,Kiffe, M.,Li, L.,Luo, F.,Luo, X.,Mi, Y.,Mistry, P.,Pearson, D.,Piaia, A.,Scheufler, C.,Terranova, R.,Weiss, A.,Zeng, J.,Zhang, H.,Zhang, J.,Zhao, M.,Dillon, M.P.,Jeay, S.,Qi, W.,Moggs, J.,Pissot-Soldermann, C.,Li, E.,Atadja, P.,Lingel, A.,Oyang, C.
Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies.
J.Med.Chem., 65:5317-5333, 2022

PubMed Abstract: Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound ) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

PubMed: 35352560
DOI: 10.1021/acs.jmedchem.1c02148

Experimental method

X-RAY DIFFRACTION (1.602 Å)