4OG7

Human menin with bound inhibitor MIV-7

4OG7 の概要

• エントリーDOI: 10.2210/pdb4og7/pdb
• 分子名称: Menin, SULFATE ION, 4-(3-{4-[(S)-cyclopentyl(hydroxy)pyridin-2-ylmethyl]piperidin-1-yl}propoxy)benzenesulfonamide, ... (7 entities in total)
• 機能のキーワード: protein binding-inhibitor complex, protein binding/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: O00255
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55844.88

構造登録者

He, S.,Senter, T.J.,Pollock, J.W.,Han, C.,Upadhyay, S.K.,Purohit, T.,Gogliotti, R.D.,Lindsley, C.W.,Cierpicki, T.,Stauffer, S.R.,Grembecka, J. (登録日: 2014-01-15, 公開日: 2014-03-05, 最終更新日: 2023-09-20)

主引用文献

He, S.,Senter, T.J.,Pollock, J.,Han, C.,Upadhyay, S.K.,Purohit, T.,Gogliotti, R.D.,Lindsley, C.W.,Cierpicki, T.,Stauffer, S.R.,Grembecka, J.
High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction.
J.Med.Chem., 57:1543-1556, 2014

PubMed Abstract: The protein-protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin-MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of ∼288000 small molecules. We determined menin-inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin-MLL interaction with IC50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules.

PubMed: 24472025
DOI: 10.1021/jm401868d

実験手法

X-RAY DIFFRACTION (2.08 Å)