Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein鈥揚rotein Interaction

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• 作者：Haibin Zhou ; Liu Liu ; Jing Huang ; Denzil Bernard ; Hacer Karatas ; Alexandro Navarro ; Ming Lei ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1113-1123
• 全文大小：638K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

Menin is an essential oncogenic cofactor for mixed lineage leukemia 1 (MLL1)-mediated leukemogenesis through its direct interaction with MLL1. Targeting the menin鈥揗LL1 protein鈥損rotein interaction represents a promising strategy to block MLL1-mediated leukemogenesis. Employing a structure-based approach and starting from a linear MLL1 octapeptide, we have designed a class of potent macrocyclic peptidomimetic inhibitors of the menin鈥揗LL1 interaction. The most potent macrocyclic peptidomimetic (MCP-1), 34, binds to menin with a K_i value of 4.7 nM and is >600 times more potent than the corresponding acyclic peptide. Compound 34 is also less peptide-like and has a lower molecular weight than the initial MLL1 peptide. Therefore, compound 34 serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin鈥揗LL1 interaction.