N³-(3-anilino-3-oxopropyl)-N³-(3-butoxypropyl)-N¹-phenyl-β-alaninamide

• 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: N³-(3-anilino-3-oxopropyl)-N³-(3-butoxypropyl)-N¹-phenyl-β-alaninamide
• 英文别名: 3-[(3-anilino-3-oxopropyl)-(3-butoxypropyl)amino]-N-phenylpropanamide
• 化学式: C₂₅H₃₅N₃O₃
• 分子量: 425.571
• InChiKey: BZZUMAUBDYSCRU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  31
• 可旋转键数：
  15
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  70.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-丁氧基丙胺 、 N-苯基丙烯酰胺 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙腈 为溶剂， 反应 16.0h， 以25%的产率得到N³-(3-anilino-3-oxopropyl)-N³-(3-butoxypropyl)-N¹-phenyl-β-alaninamide
  参考文献：
  名称：

  A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia

  摘要：

  Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 mu M], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.

  DOI：

  10.1021/acs.jmedchem.9b00145

文献信息

• A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia
  作者：Nagore I. Marín-Ramos、Moisés Balabasquer、Francisco J. Ortega-Nogales、Iván R. Torrecillas、Ana Gil-Ordóñez、Beatriz Marcos-Ramiro、Pedro Aguilar-Garrido、Ian Cushman、Antonio Romero、Francisco J. Medrano、Consuelo Gajate、Faustino Mollinedo、Mark R. Philips、Mercedes Campillo、Miguel Gallardo、Mar Martín-Fontecha、María L. López-Rodríguez、Silvia Ortega-Gutiérrez

  DOI：10.1021/acs.jmedchem.9b00145

  日期：2019.7.11

  Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 mu M], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.