5DB2: Menin In Complex With Mi-389

Citation:
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.
PDB ID: 5DB2Download
MMDB ID: 137865
PDB Deposition Date: 2015/8/20
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 1.54  Å
Source Organism:
Similar Structures:
Biological Unit for 5DB2: monomeric; determined by author and by software (PISA)
Molecular Components in 5DB2
Label Count Molecule
Protein (1 molecule)
1
Menin(Gene symbol: MEN1)
Molecule annotation
Chemicals (11 molecules)
1
1
2
3
3
1
4
5
5
1
* Click molecule labels to explore molecular sequence information.

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