(3-(6-(2-甲氧基苯基)嘧啶-4-基氨基)苯基)甲烷磺酰胺 | 1073485-20-7

• 物质功能分类: 生物化工 - 抑制剂 - 细胞周期(Cell Cycle)
• 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: (3-(6-(2-甲氧基苯基)嘧啶-4-基氨基)苯基)甲烷磺酰胺
• 英文名称: LDC000067
• 英文别名: 3-[[6-(2-methoxyphenyl)-4-pyrimidinyl]amino]-Benzenemethanesulfonamide；LDC067；1073485-20-7P；(3-((6-(2-Methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide；[3-[[6-(2-methoxyphenyl)pyrimidin-4-yl]amino]phenyl]methanesulfonamide
• CAS: 1073485-20-7
• 化学式: C₁₈H₁₈N₄O₃S
• 分子量: 370.432
• InChiKey: GGQCIOOSELPMBB-UHFFFAOYSA-N

物化性质

• 沸点：
  604.1±65.0 °C(Predicted)
• 密度：
  1.360±0.06 g/cm3(Predicted)
• 溶解度：
  不溶于水；不溶于乙醇； ≥18.52 mg/mL，溶于 DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  116
• 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

制备方法与用途

生物活性

LDC000067（LDC067）是一种高度选择性的CDK9抑制剂，其IC50值为44 nM，在作用于CDK2/1/4/6/7的选择性上分别高出了55倍、125倍、210倍、大于227倍及大于227倍。

靶点

Target	Value
CDK9 (细胞自由体系测定)	44 nM
CDK2 (细胞自由体系测定)	2.441 μM

体外研究

LDC000067能够减少胚胎干细胞（mESCs）中Ser2位点磷酸化，进而诱导p53的活化，并导致细胞凋亡。此外，该化合物还表现出剂量依赖性地抑制P-TEFb依赖性的RNA从头合成。

反应信息

• 作为产物：
  描述：

  3-氨基-苯甲烷磺酰胺 、 4-chloro-6-(2-methoxyphenyl)pyrimidine 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以71%的产率得到(3-(6-(2-甲氧基苯基)嘧啶-4-基氨基)苯基)甲烷磺酰胺
  参考文献：
  名称：

  Characterization of molecular and cellular functions of the cyclin-dependent kinase CDK9 using a novel specific inhibitor

  摘要：

  Background and PurposeThe cyclin‐dependent kinase CDK9 is an important therapeutic target but currently available inhibitors exhibit low specificity and/or narrow therapeutic windows. Here we have used a new highly specific CDK9 inhibitor, LDC000067 to interrogate gene control mechanisms mediated by CDK9.Experimental ApproachThe selectivity of LDC000067 was established in functional kinase assays. Functions of CDK9 in gene expression were assessed with in vitro transcription experiments, single gene analyses and genome‐wide expression profiling. Cultures of mouse embryonic stem cells, HeLa cells, several cancer cell lines, along with cells from patients with acute myelogenous leukaemia were also used to investigate cellular responses to LDC000067.Key ResultsThe selectivity of LDC000067 for CDK9 over other CDKs exceeded that of the known inhibitors flavopiridol and DRB. LDC000067 inhibited in vitro transcription in an ATP‐competitive and dose‐dependent manner. Gene expression profiling of cells treated with LDC000067 demonstrated a selective reduction of short‐lived mRNAs, including important regulators of proliferation and apoptosis. Analysis of de novo RNA synthesis suggested a wide ranging positive role of CDK9. At the molecular and cellular level, LDC000067 reproduced effects characteristic of CDK9 inhibition such as enhanced pausing of RNA polymerase II on genes and, most importantly, induction of apoptosis in cancer cells.Conclusions and ImplicationsOur study provides a framework for the mechanistic understanding of cellular responses to CDK9 inhibition. LDC000067 represents a promising lead for the development of clinically useful, highly specific CDK9 inhibitors.

  DOI：

  10.1111/bph.12408

文献信息

• 4, 6-DISUBSTITUTED AMINOPYRIMIDINE DERIVATIVES AS INHIBITORS OF PROTEIN KINASES
  申请人：Wabnitz Philipp

  公开号：US20110306602A1

  公开（公告）日：2011-12-15

  The present invention relates to inhibitors of general Formula (I) of cyclin-dependent kinases and therapeutic applications thereof. Furthermore, the invention relates to compounds for preventing and/or treating any type of pain, inflammatory disorders, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases and neurodegenerative diseases.

  本发明涉及一般公式(I)的细胞周期依赖性激酶抑制剂及其治疗应用。此外，本发明还涉及用于预防和/或治疗任何类型的疼痛、炎症性疾病、免疫性疾病、增殖性疾病、传染性疾病、心血管疾病和神经退行性疾病的化合物。
• 4,6-DISUBSTITUTED AMINOPYRIMIDINE DERIVATIVES AS INHIBITORS OF PROTEIN KINASES
  申请人：Ingenium Pharmaceuticals GmbH

  公开号：US20130338147A1

  公开（公告）日：2013-12-19

  The present invention relates to inhibitors of cyclin-dependent kinases and therapeutic applications thereof. Furthermore, the invention relates to methods of preventing and/or treating any type of pain, inflammatory disorders, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases and neurodegenerative diseases comprising the administration of an effective amount of at least one inhibitor of cyclin-dependent kinases.

  本发明涉及抑制细胞周期依赖性激酶及其治疗应用的药物。此外，本发明涉及通过给予至少一种细胞周期依赖性激酶抑制剂的有效剂量来预防和/或治疗任何类型的疼痛、炎症性疾病、免疫性疾病、增殖性疾病、传染性疾病、心血管疾病和神经退行性疾病的方法。
• CDK9 inhibitors in the treatment of midline carcinoma
  申请人：Lead Discovery Center GmbH

  公开号：EP2561867A1

  公开（公告）日：2013-02-27

  The present invention relates to a CDK9 inhibitor, especially a selective CDK9 inhibitor, for use in treating, ameliorating and/or preventing midline carcinoma. Also corresponding methods for treating, preventing or ameliorating midline carcinoma are subject of the present invention. Preferably, NUT midline carcinoma is treated with the CDK9 inhibitors in accordance with the present invention.

  本发明涉及一种CDK9抑制剂，特别是一种选择性CDK9抑制剂，用于治疗、改善和/或预防中线癌。此外，治疗、预防或改善中线癌的相应方法也是本发明的主题。优选地，根据本发明用CDK9抑制剂治疗NUT中线癌。
• Susceptibility to selective CDK9 inhibitors
  申请人：Lead Discovery Center GmbH

  公开号：EP2562265A1

  公开（公告）日：2013-02-27

  The present invention relates to a method of selecting (a) cell(s), (a) tissue(s) or (a) cell culture(s) with susceptibility to a selective CDK9 inhibitor. Also a method for determining the responsiveness of a mammalian tumor cell or cancer cell to treatment with a selective CDK9 inhibitor is described herein. In particular, the present invention provides for an in vitro method for the identification of a responder for or a patient sensitive to a selective CDK9 inhibitor, whereby the patient is suspected to suffer from NUT midline carcinoma (NMC). The present invention also relates to a method of monitoring or predicting the efficacy of a treatment of NUT midline carcinoma (NMC), wherein treatment with a selective CDK9 inhibitor is in particular envisaged. Also the use of a (transgenic) non-human animal or a (transgenic) cell having at least one rearrangement in the NUT gene for screening and/or validation of a medicament for the treatment NUT midline carcinoma (NMC) is described. Furthermore, a kit useful for carrying out the methods described herein as well as an oligo- or polynucleotide capable of detecting rearrangements in the NUT gene are provide.

  本发明涉及一种选择对选择性 CDK9 抑制剂敏感的细胞、组织或细胞培养物的方法。本文还描述了一种确定哺乳动物肿瘤细胞或癌细胞对选择性 CDK9 抑制剂治疗的反应性的方法。特别是，本发明提供了一种体外方法，用于鉴定对选择性 CDK9 抑制剂敏感的应答者或患者，其中患者被怀疑患有 NUT 中线癌（NMC）。本发明还涉及一种监测或预测NUT中线癌（NMC）疗效的方法，其中特别设想了用选择性CDK9抑制剂进行治疗。此外，还描述了使用至少有一个 NUT 基因重排的（转基因）非人类动物或（转基因）细胞来筛选和/或验证治疗 NUT 中线癌（NMC）的药物。此外，还提供了用于实施本文所述方法的试剂盒以及能够检测 NUT 基因重排的寡核苷酸或多核苷酸。
• Methods for treating epithelian mesenchymal transition related diseases
  申请人：Tian Bing

  公开号：US10292986B2

  公开（公告）日：2019-05-21

  Certain embodiments are directed to methods of treating chronic lung diseases in a subject comprising administering to a subject diagnosed with, exhibiting symptoms of, or at risk of developing a chronic lung disease a therapeutically effective amount of a BRD4 inhibitor or a CDK9 inhibitor to the subject.

  某些实施方案涉及治疗受试者慢性肺部疾病的方法，包括向被诊断患有慢性肺部疾病、表现出慢性肺部疾病症状或有患慢性肺部疾病风险的受试者施用治疗有效量的BRD4抑制剂或CDK9抑制剂。