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High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein Interaction
[Image: see text] 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-molec...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983337/ https://www.ncbi.nlm.nih.gov/pubmed/24472025 http://dx.doi.org/10.1021/jm401868d |
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author | He, Shihan Senter, Timothy J. Pollock, Jonathan Han, Changho Upadhyay, Sunil Kumar Purohit, Trupta Gogliotti, Rocco D. Lindsley, Craig W. Cierpicki, Tomasz Stauffer, Shaun R. Grembecka, Jolanta |
author_facet | He, Shihan Senter, Timothy J. Pollock, Jonathan Han, Changho Upadhyay, Sunil Kumar Purohit, Trupta Gogliotti, Rocco D. Lindsley, Craig W. Cierpicki, Tomasz Stauffer, Shaun R. Grembecka, Jolanta |
author_sort | He, Shihan |
collection | PubMed |
description | [Image: see text] 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 IC(50) = 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. |
format | Online Article Text |
id | pubmed-3983337 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American
Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-39833372015-01-28 High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein Interaction He, Shihan Senter, Timothy J. Pollock, Jonathan Han, Changho Upadhyay, Sunil Kumar Purohit, Trupta Gogliotti, Rocco D. Lindsley, Craig W. Cierpicki, Tomasz Stauffer, Shaun R. Grembecka, Jolanta J Med Chem [Image: see text] 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 IC(50) = 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. American Chemical Society 2014-01-28 2014-02-27 /pmc/articles/PMC3983337/ /pubmed/24472025 http://dx.doi.org/10.1021/jm401868d Text en Copyright © 2014 American Chemical Society |
spellingShingle | He, Shihan Senter, Timothy J. Pollock, Jonathan Han, Changho Upadhyay, Sunil Kumar Purohit, Trupta Gogliotti, Rocco D. Lindsley, Craig W. Cierpicki, Tomasz Stauffer, Shaun R. Grembecka, Jolanta High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein Interaction |
title | High-Affinity Small-Molecule
Inhibitors of the Menin-Mixed
Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein
Interaction |
title_full | High-Affinity Small-Molecule
Inhibitors of the Menin-Mixed
Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein
Interaction |
title_fullStr | High-Affinity Small-Molecule
Inhibitors of the Menin-Mixed
Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein
Interaction |
title_full_unstemmed | High-Affinity Small-Molecule
Inhibitors of the Menin-Mixed
Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein
Interaction |
title_short | High-Affinity Small-Molecule
Inhibitors of the Menin-Mixed
Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein–Protein
Interaction |
title_sort | high-affinity small-molecule
inhibitors of the menin-mixed
lineage leukemia (mll) interaction closely mimic a natural protein–protein
interaction |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983337/ https://www.ncbi.nlm.nih.gov/pubmed/24472025 http://dx.doi.org/10.1021/jm401868d |
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