5DB3

Menin in complex with MI-574

5DB3 の概要

• エントリーDOI: 10.2210/pdb5db3/pdb
• 関連するPDBエントリー: 5DB0 5DB1 5DB2
• 分子名称: Menin, DIMETHYL SULFOXIDE, TETRAETHYLENE GLYCOL, ... (7 entities in total)
• 機能のキーワード: protein binding, protein binding-inhibitor complex, protein binding/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56278.10

構造登録者

Pollock, J.,Borkin, D.,Cierpicki, T.,Grembecka, J. (登録日: 2015-08-20, 公開日: 2016-03-30, 最終更新日: 2024-03-06)

主引用文献

Borkin, D.,Pollock, J.,Kempinska, K.,Purohit, T.,Li, X.,Wen, B.,Zhao, T.,Miao, H.,Shukla, S.,He, M.,Sun, D.,Cierpicki, T.,Grembecka, J.
Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL).
J.Med.Chem., 59:892-913, 2016

PubMed Abstract: Development of potent small molecule inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compounds, which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compound 1 (MI-136) to identify compounds suitable for in vivo studies in mice. This work resulted in the identification of compound 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications.

PubMed: 26744767
DOI: 10.1021/acs.jmedchem.5b01305

実験手法

X-RAY DIFFRACTION (1.71 Å)