4X5Z

menin in complex with MI-136

Summary for 4X5Z

• Entry DOI: 10.2210/pdb4x5z/pdb
• Related: 4X5Y
• Descriptor: Menin, SULFATE ION, 5-[(4-{[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)methyl]-1H-indole-2-carbonitrile, ... (7 entities in total)
• Functional Keywords: protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 55837.55

Authors

Pollock, J.,Borkin, D.,Cierpicki, T.,Grembecka, J. (deposition date: 2014-12-06, release date: 2015-04-15, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.86 Å)