4X5Y

Menin in complex with MI-503

4X5Y の概要

• エントリーDOI: 10.2210/pdb4x5y/pdb
• 分子名称: Menin, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[(4-{[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)methyl]-1H-indole-2-carbonitrile, DIMETHYL SULFOXIDE, ... (8 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); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56152.04

構造登録者

Pollock, J.,Borkin, D.,Cierpicki, T.,Grembecka, J. (登録日: 2014-12-06, 公開日: 2015-04-15, 最終更新日: 2023-12-27)

主引用文献

Borkin, D.,He, S.,Miao, H.,Kempinska, K.,Pollock, J.,Chase, J.,Purohit, T.,Malik, B.,Zhao, T.,Wang, J.,Wen, B.,Zong, H.,Jones, M.,Danet-Desnoyers, G.,Guzman, M.L.,Talpaz, M.,Bixby, D.L.,Sun, D.,Hess, J.L.,Muntean, A.G.,Maillard, I.,Cierpicki, T.,Grembecka, J.
Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo.
Cancer Cell, 27:589-602, 2015

PubMed Abstract: Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

PubMed: 25817203
DOI: 10.1016/j.ccell.2015.02.016

実験手法

X-RAY DIFFRACTION (1.59 Å)