High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein鈥揚rotein Interaction

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• 作者：Shihan He ; Timothy J. Senter ; Jonathan Pollock ; Changho Han ; Sunil Kumar Upadhyay ; Trupta Purohit ; Rocco D. Gogliotti ; Craig W. Lindsley ; Tomasz Cierpicki ; Shaun R. Stauffer ; Jolanta Grembecka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1543-1556
• 全文大小：730K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

The protein鈥損rotein 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鈥揗LL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of 288000 small molecules. We determined menin鈥搃nhibitor 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鈥揗LL 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.