4'-(环丙基甲基)-N2-4-吡啶基[4,5'-联嘧啶]-2,2'-二胺 | 1383716-40-2

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 4'-(环丙基甲基)-N2-4-吡啶基[4,5'-联嘧啶]-2,2'-二胺
• 英文名称: PIK-III
• 英文别名: 4'-(cyclopropylmethyl)-N²-(pyridin-4-yl)-[4,5'-'bipyrimidine]-2,2'-diamine；4-(cyclopropylmethyl)-5-[2-(pyridin-4-ylamino)pyrimidin-4-yl]pyrimidin-2-amine
• CAS: 1383716-40-2
• 化学式: C₁₇H₁₇N₇
• 分子量: 319.369
• InChiKey: XXSDLQLNIVFIJI-UHFFFAOYSA-N

物化性质

• 沸点：
  657.4±65.0 °C(Predicted)
• 密度：
  1.380±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO 中≥31.9 mg/mL；不溶于水；不溶于乙醇

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20℃

制备方法与用途

生物活性

PIK-III (VPS34-IN2) 是一种选择性 VPS34 酶活性抑制剂，它能够抑制细胞自噬以及 LC3 的重新脂化，从而稳定自噬底物。其对 VPS34 和 PI(3)Kδ 的 IC50 值分别为 0.018 μM 和 1.2 μM。

靶点

Target	Value
Vps34 (Cell-free assay)	0.018μM
PI3Kδ (Cell-free assay)	1.2μM

体外研究

VPS34 酶活性对于哺乳动物细胞中 LC3 的脂化是必要的。PIK-III 在哺乳动物细胞中是一种强效的自噬抑制剂，能够抑制 LC3 的脂化。在 H4 细胞中，当自噬反应被 mTOR 抑制剂 AZD8055 诱导时，PIK-III 可以抑制自溶酶体的形成，并在基础水平上提高 LC3 的胞质信号。在 CCCP-诱导的线粒体自噬模型中，PIK-III 抑制了线粒体的清除。在 H4 和 PSN1 细胞中，PIK-III 处理导致 LC3-I 水平上升。而在 Panc10.05 细胞中，PIK-III 同时升高了 LC3-II 和 LC3-I 的水平。

反应信息

• 作为产物：
  描述：

  4-氨基吡啶 、 4'-(cyclopropylmethyl)-2-(methylsulfinyl)-[4,5'-bipyrimidin]-2'-amine 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以6%的产率得到4'-(环丙基甲基)-N2-4-吡啶基[4,5'-联嘧啶]-2,2'-二胺
  参考文献：
  名称：

  PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells

  摘要：

  背景：尽管近年来治疗方面取得了进展，但化疗耐药仍然是结直肠癌（CRC）临床管理中的重要问题。癌症干细胞（CSCs）在治疗耐药中起着核心作用。因此，清除CSCs对于有效的CRC治疗至关重要；然而，这样的策略受到限制。自噬促进了对癌症治疗的耐药性；然而，自噬是否保护CSCs以促进对CRC治疗的耐药性尚不明确。此外，由于羟氯喹的临床试验并不成功，因此需要特异性和有效的自噬抑制剂。方法：使用结肠癌细胞和肿瘤体。进行自噬通量的荧光报告基础分析，球体和侧向群体（SP）培养，以及qPCR。我们合成了36-077，一种有效的PIK3C3/VPS34激酶抑制剂，用于抑制自噬。使用5-氟尿嘧啶（5-FU）和36-077进行联合治疗。结果：5-FU治疗仅在部分受治疗的结肠癌细胞中诱导自噬。这些富含自噬的细胞还显示出CSC标记物的表达增加。与36-077联合治疗显著提高了5-FU治疗的疗效。机制研究显示，联合治疗抑制了GSK-3β/Wnt/β-连环蛋白信号通路以抑制CSC种群。结论：自噬通过特异性促进GSK-3β/Wnt/β-连环蛋白信号通路，从而促进CSC存活，从而促进CRC治疗的耐药性，而PIK3C3/VPS34抑制剂36-077有助于促进CRC治疗的疗效。

  DOI：

  10.3390/cancers13092168

文献信息

• [EN] BI-HETEROARYL COMPOUNDS AS VPS34 INHIBITORS<br/>[FR] COMPOSÉS BI-HÉTÉROARYLES EN TANT QU'INHIBITEURS DE VPS34
  申请人：NOVARTIS AG

  公开号：WO2012085815A1

  公开（公告）日：2012-06-28

  The present invention includes novel methods of treating a disease or disorder characterized by hyperactivity of Vps34, and compound as Vps34 inhibitors; particularly compounds of Formula I or a pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Vps34 inhibition, particularly hyperproliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable salts thereof.

  本发明涉及治疗由Vps34高活性特征的疾病或紊乱的新方法，以及作为Vps34抑制剂的化合物；特别是公式I的化合物或其药用盐，以及治疗与Vps34抑制相关的疾病、紊乱或综合症的方法，特别是高增殖性疾病。本发明还包括包括公式I化合物及其药用盐的药物组合物。
• BI-HETEROARYL COMPOUNDS AS VPS34 INHIBITORS
  申请人：Taracido Ivan Cornella

  公开号：US20140155402A1

  公开（公告）日：2014-06-05

  The present invention includes novel methods of treating a disease or disorder characterized by hyperactivity of Vps34, and compound as Vps34 inhibitors; particularly compounds of Formula I: or a pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Vps34 inhibition, particularly hyperproliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable salts thereof.

  本发明包括治疗由Vps34高活性所特征的疾病或障碍的新方法，以及作为Vps34抑制剂的化合物；特别是公式I的化合物：或其药学上可接受的盐，以及治疗与Vps34抑制相关的疾病、障碍或综合症的方法，特别是增殖过度性疾病的方法。本发明还包括包括公式I的化合物和其药学上可接受的盐的药物组合物。
• Bi-heteroaryl compounds as Vps34 inhibitors
  申请人：Taracido Ivan Cornella

  公开号：US08685993B2

  公开（公告）日：2014-04-01

  The present invention includes novel methods of treating a disease or disorder characterized by hyperactivity of Vps34, and compound as Vps34 inhibitors; particularly compounds of Formula I or a pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Vps34 inhibition, particularly hyperproliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable salts thereof.

  本发明包括治疗由Vps34过度活化引起的疾病或障碍的新方法，以及作为Vps34抑制剂的化合物；特别是公式I的化合物或其药学上可接受的盐，以及治疗与Vps34抑制相关的疾病、障碍或综合征的方法，特别是增殖过度性疾病。本发明还包括包括公式I的化合物及其药学上可接受的盐的制药组合物。
• Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy <i>in Vivo</i>
  作者：Ayako Honda、Edmund Harrington、Ivan Cornella-Taracido、Pascal Furet、Mark S. Knapp、Meir Glick、Ellen Triantafellow、William E. Dowdle、Dmitri Wiedershain、Wieslawa Maniara、Christine Moore、Peter M. Finan、Lawrence G. Hamann、Brant Firestone、Leon O. Murphy、Erin P. Keaney

  DOI：10.1021/acsmedchemlett.5b00335

  日期：2016.1.14

  Autophagy is a dynamic process that regulates lysosomal-dependent degradation of cellular components. Until recently the study of autophagy has been hampered by the lack of reliable pharmacological tools, but selective inhibitors are now available to modulate the PI 3-kinase VPS34, which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors, their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models.
• Optimized Method for Treating and Curing Arthritis, Diabetes, Multiple Sclerosis and Other Autoimmune Disease
  申请人：Postrel Richard

  公开号：US20190070166A1

  公开（公告）日：2019-03-07

  The present invention teaches a method, system and process for curing, treating and diagnosing arthritis, diabetes and other related autoimmune diseases. By intercepting and mitigating the disease process at the point of origination prevents the disease from developing and stops the lineage of cells causing disease symptoms. This fundamental system addresses cellular events where the immune reaction is emerging thereby preventing advance of the cascade that feeds the disease. Modulating activity of the errant protein at this initiating point in the immune response blocks the autoimmune cascade and prevents formation of secondary and tertiary effects that will characterize the disease. As the cascade progresses, the number of participating enzymes and pathways compounds so that each progression step further from the initiation point requires increasingly complex therapies. Thus, by treating the primary cause, secondary and tertiary symptoms do not appear. This avoids the side effects observed in multi-faceted approaches presently used to manage the disease symptoms rather than disease causation.