KRM-191 | 1055193-57-1

• 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: KRM-191
• 英文别名: KRM-0191；3-(2-Ethoxycarbonylmethyl-3,5-dioxo-[1,2,4]thiadiazolidin-4-yl)-benzoic acid ethyl ester；ethyl 3-[2-(2-ethoxy-2-oxoethyl)-3,5-dioxo-1,2,4-thiadiazolidin-4-yl]benzoate
• CAS: 1055193-57-1
• 化学式: C₁₅H₁₆N₂O₆S
• 分子量: 352.368
• InChiKey: KYVDZJGBGUEPQR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  119
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-乙氧基羰基苯异硫氰酸酯 在 氯 作用下， 以 正己烷 为溶剂， 生成 KRM-191
  参考文献：
  名称：

  Identification of small molecules that inhibit GSK-3β through virtual screening

  摘要：

  Glycogen synthase kinase-3 beta (GSK-3 beta) is involved in glycogen metabolism, neuronal cell development, osteoblast differentiation. Small molecule inhibitors of GSK-3 beta have various therapeutic potential for the treatment of diabetes type II, bipolar disorders, stroke and chronic in. ammatory disease.To identify GSK-3 beta inhibitors with novel scaffold from chemical library, we primarily screened out putative inhibitors through computer modeling and subsequently evaluated the inhibitory activity of selected compounds against GSK-3 beta by in vitro Z'-LYTE (TM) assay. A series of compound KRMs strongly inhibited phosphorylation of its substrate with IC50 value of approximately 0.5 mu M. Also, we demonstrated that KRM-189 and KRM-191 competed with ATP for GSK-3 beta, leading to decreased V-max and constant Km with increasing concentrations of ATP as determined from Lineweaver-Berk equation. Moreover, they showed the selectivity for GSK-3 beta over other kinases with IC50 values of 2 to 10 mu M or more Incubation of cells with KRM-191 with highly selective and potent inhibitory activity caused accumulation of beta-catenin, downstream of GSK-3 beta signaling pathway, indicating that small molecule can prevent degradation of beta-catenin via GSK-3 beta inhibition. Our results suggest that modeling in combination with in vitro assays can be used for the identification of selective and potent inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.10.120

文献信息

• Identification of small molecules that inhibit GSK-3β through virtual screening
  作者：Nam Sook Kang、Gil Nam Lee、Chi Hyun Kim、Myung Ae Bae、Ikyon Kim、Young Sik Cho

  DOI：10.1016/j.bmcl.2008.10.120

  日期：2009.1

  Glycogen synthase kinase-3 beta (GSK-3 beta) is involved in glycogen metabolism, neuronal cell development, osteoblast differentiation. Small molecule inhibitors of GSK-3 beta have various therapeutic potential for the treatment of diabetes type II, bipolar disorders, stroke and chronic in. ammatory disease.To identify GSK-3 beta inhibitors with novel scaffold from chemical library, we primarily screened out putative inhibitors through computer modeling and subsequently evaluated the inhibitory activity of selected compounds against GSK-3 beta by in vitro Z'-LYTE (TM) assay. A series of compound KRMs strongly inhibited phosphorylation of its substrate with IC50 value of approximately 0.5 mu M. Also, we demonstrated that KRM-189 and KRM-191 competed with ATP for GSK-3 beta, leading to decreased V-max and constant Km with increasing concentrations of ATP as determined from Lineweaver-Berk equation. Moreover, they showed the selectivity for GSK-3 beta over other kinases with IC50 values of 2 to 10 mu M or more Incubation of cells with KRM-191 with highly selective and potent inhibitory activity caused accumulation of beta-catenin, downstream of GSK-3 beta signaling pathway, indicating that small molecule can prevent degradation of beta-catenin via GSK-3 beta inhibition. Our results suggest that modeling in combination with in vitro assays can be used for the identification of selective and potent inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.