4OG6
Human menin with bound inhibitor MIV-4
Summary for 4OG6
| Entry DOI | 10.2210/pdb4og6/pdb |
| Related | 4OG3 4OG4 4OG5 4OG7 4OG8 |
| Descriptor | Menin, SULFATE ION, 4-(3-{4-[(R)-cyclopentyl(3-fluorophenyl)hydroxymethyl]piperidin-1-yl}propoxy)benzonitrile, ... (7 entities in total) |
| Functional Keywords | protein binding/inhibitor, protein binding-inhibitor complex |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus: O00255 |
| Total number of polymer chains | 1 |
| Total formula weight | 55957.99 |
| Authors | 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. (deposition date: 2014-01-15, release date: 2014-03-05, Last modification date: 2023-09-20) |
| Primary citation | 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 Cited by 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: 24472025DOI: 10.1021/jm401868d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.49 Å) |
Structure validation
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