methyl 3-methoxy-4-(1H-pyrazol-1-yl)benzene-1-sulfonyl chloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: methyl 3-methoxy-4-(1H-pyrazol-1-yl)benzene-1-sulfonyl chloride
• 英文别名: 3-Methoxy-4-pyrazol-1-yl-benzenesulfonyl chloride；3-methoxy-4-pyrazol-1-ylbenzenesulfonyl chloride
• 化学式: C₁₀H₉ClN₂O₃S
• 分子量: 272.712
• InChiKey: MFUKFZKTECQACP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  69.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氟-5-硝基苯甲醚 在 盐酸 、 铁粉 、 potassium carbonate 、 氯化铵 、 溶剂黄146 、 sodium nitrite 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 46.25h， 生成 methyl 3-methoxy-4-(1H-pyrazol-1-yl)benzene-1-sulfonyl chloride
  参考文献：
  名称：

  [EN] INHIBITING UBIQUITIN SPECIFIC PEPTIDASE 9X
  [FR] INHIBITION DE LA PEPTIDASE 9X SPÉCIFIQUE DE L'UBIQUITINE

  摘要：

  该披露提供了一种新颖的化合物，可用作泛素特异性蛋白酶9X（USP9X）的抑制剂。抑制USP9X的化合物在治疗与调节USP9X相关的疾病和紊乱，如癌症，方面是有用的。

  公开号：

  WO2020139916A1

文献信息

• INHIBITING UBIQUITIN SPECIFIC PEPTIDASE 9X
  申请人：FORMA Therapeutics, Inc.

  公开号：US20220041597A1

  公开（公告）日：2022-02-10

  FLT3-ITD and FLT3-TKD are the most frequent mutations in acute myeloid leukemia (AML) with the former associated with a poor prognosis. Here we show that inhibition of the deubiquitinase USP9X by its inhibitor WP1130 or EOAI3402143 (G9) induces apoptosis preferentially in cells transformed by these mutant kinases, including FLT3-ITD-positive AML cell line MV4-11 and primary AML cells. Mechanistically, WP1130 induced aggresomal translocation of the mutant kinases, particularly FLT3-ITD in its activated and autophosphorylated conformation, to block the downstream signaling events, which was aggravated by knock down of USP9X. Moreover, USP9X physically associated with FLT3-ITD to inhibit its K63-linked polyubiquitination, while FLT3-ITD induced tyrosine phosphorylation and degradation of USP9X through the ubiquitin/proteasome pathway. WP1130 or G9 also induced oxidative stress to stimulate stress-related MAP kinase pathways and DNA damage responses to activate in cooperation with inhibition of FLT3-ITD signaling the intrinsic mitochondria-mediated apoptotic pathway, which was synergistically enhanced by BH3 mimetics and prevented by overexpression of Bcl-xL or Mcl-1. Thus, USP9X represents a promising target for novel therapies against therapy-resistant FLT3-ITD-positive AML.