6-chloro-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine | 1404437-70-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6-chloro-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
• 英文别名: 6-chloro-1-(4-methoxyphenyl)-pyrazolo[3,4-d]pyrimidine；6-Chloro-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine；6-chloro-1-(4-methoxyphenyl)pyrazolo[3,4-d]pyrimidine
• CAS: 1404437-70-2
• 化学式: C₁₂H₉ClN₄O
• 分子量: 260.683
• InChiKey: PLSRSHMLMIXOSH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  52.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺 、 6-chloro-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine 在 盐酸 作用下， 以 1,4-二氧六环 、 异丙醇 为溶剂， 反应 1.5h， 以43%的产率得到N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine
  参考文献：
  名称：

  A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells

  摘要：

  The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the chemical probe ML281 that showed low nanomolar inhibition of purified recombinant STK33 and a distinct selectivity profile as compared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 mu M), ML281 had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using small-molecule STK33 inhibitors. Small molecules having different chemical structures and kinase-selectivity profiles are needed to fully understand the role of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable addition to small-molecule probes of STK33.

  DOI：

  10.1021/ml300246r
• 作为产物：
  描述：

  4-甲氧基苯硼酸 、 6-氯-1H-吡唑并[3,4-D]嘧啶 在 吡啶 、 copper diacetate 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 以27%的产率得到6-chloro-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells

  摘要：

  The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the chemical probe ML281 that showed low nanomolar inhibition of purified recombinant STK33 and a distinct selectivity profile as compared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 mu M), ML281 had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using small-molecule STK33 inhibitors. Small molecules having different chemical structures and kinase-selectivity profiles are needed to fully understand the role of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable addition to small-molecule probes of STK33.

  DOI：

  10.1021/ml300246r

文献信息

• Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors
  作者：Ulrich Grädler、Michael Busch、Birgitta Leuthner、Michael Raba、Lars Burgdorf、Martin Lehmann、Nina Linde、Christina Esdar

  DOI：10.1016/j.bmcl.2020.127551

  日期：2020.11

  Triazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC-loop and αC-helix conformations suggesting a potential structural link towards MK5 interaction via the FHIEDE motif. The inhibitors also showed sub-100 nM potencies in a cellular ERK3 NanoBRET assay and with excellent correlation to the biochemical IC₅₀s. This novel series provides valuable tool compounds to further investigate the biological function and activation mechanism of ERK3.
• [EN] ANTIVIRAL PYRIMIDINES<br/>[FR] PYRIMIDINES ANTIVIRALES
  申请人：PROGENICS PHARM INC

  公开号：WO2010118367A2

  公开（公告）日：2010-10-14

  Disclosed herein are novel compounds comprising substituted pyrimidines, pyrazolopyrimtdines, and imidazolopyrimidines, the syntheses thereof, and compositions thereof, including pharmaceutical compositions, comprising the novel pyrimidines, pyrazolopyrimtdines, imidazolpyrimidines and related compounds. Such compounds function to inhibit entry of viruses of the Flaviviridae family, including Hepatitis C virus (HCV), into cells that are susceptible to virus infection. These compounds are useful for the treatment, therapy and/or prophylaxis of viral diseases and infection, including HCV infection.
• A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells
  作者：Michel Weïwer、James Spoonamore、Jingqiang Wei、Boris Guichard、Nathan T. Ross、Kristina Masson、Whitney Silkworth、Sivaraman Dandapani、Michelle Palmer、Christina A. Scherer、Andrew M. Stern、Stuart L. Schreiber、Benito Munoz

  DOI：10.1021/ml300246r

  日期：2012.12.13

  The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the chemical probe ML281 that showed low nanomolar inhibition of purified recombinant STK33 and a distinct selectivity profile as compared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 mu M), ML281 had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using small-molecule STK33 inhibitors. Small molecules having different chemical structures and kinase-selectivity profiles are needed to fully understand the role of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable addition to small-molecule probes of STK33.
• Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
  作者：Jeffrey J. Jackson、Grant M. Shibuya、Buvana Ravishankar、Lavanya Adusumilli、Delia Bradford、Dirk G. Brockstedt、Cyril Bucher、Minna Bui、Cynthia Cho、Christoph Colas、Gene Cutler、Adrian Dukes、Xinping Han、Dennis X. Hu、Scott Jacobson、Paul D. Kassner、George E. Katibah、Michelle Yoo Min Ko、Urvi Kolhatkar、Paul R. Leger、Anqi Ma、Lisa Marshall、Jack Maung、Andrew A. Ng、Akinori Okano、Deepa Pookot、Daniel Poon、Chandru Ramana、Maureen K. Reilly、Omar Robles、Jacob B. Schwarz、Anton A. Shakhmin、Hunter P. Shunatona、Raashi Sreenivasan、Parcharee Tivitmahaisoon、Mengshu Xu、Thant Zaw、David J. Wustrow、Mikhail Zibinsky

  DOI：10.1021/acs.jmedchem.2c00736

  日期：2022.10.13