5DB2

Menin in complex with MI-389

Summary for 5DB2

• Entry DOI: 10.2210/pdb5db2/pdb
• Related: 5DB0 5DB1 5DB3
• Descriptor: Menin, 2-{2-cyano-5-[(4-{[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)methyl]-1H-indol-1-yl}aceta mide, DIMETHYL SULFOXIDE, ... (7 entities in total)
• Functional Keywords: protein binding, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 56112.85

Authors

Pollock, J.,Dmitry, B.,Cierpicki, T.,Grembecka, J. (deposition date: 2015-08-20, release date: 2016-03-30, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.54 Å)