2-Ethyl-2-(isobutyrylamino)butyric acid | 1421263-51-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-Ethyl-2-(isobutyrylamino)butyric acid
• 英文别名: 2-ethyl-2-(2-methylpropanoylamino)butanoic acid
• CAS: 1421263-51-5
• 化学式: C₁₀H₁₉NO₃
• 分子量: 201.266
• InChiKey: KXOYWCPMUDHRMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-Ethyl-2-(isobutyrylamino)butyric acid 在 2-chlorotrityl chloride polystyrene resin 、 1,4-dithio-D,L-threitol 、 水 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 N-benzhydryl-1-[[(2S)-5-(diaminomethylideneamino)-2-[[2-ethyl-2-(2-methylpropanoylamino)butanoyl]amino]pentanoyl]amino]cyclopentane-1-carboxamide;2,2,2-trifluoroacetic acid
  参考文献：
  名称：

  High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein–Protein Interaction

  摘要：

  Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K-i < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics M complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM 102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.

  DOI：

  10.1021/ja306028q

文献信息

• High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein–Protein Interaction
  作者：Hacer Karatas、Elizabeth C. Townsend、Fang Cao、Yong Chen、Denzil Bernard、Liu Liu、Ming Lei、Yali Dou、Shaomeng Wang

  DOI：10.1021/ja306028q

  日期：2013.1.16

  Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K-i < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics M complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM 102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.