4-[[4-氨基-5-氰基-6-[(1,1-二甲基乙基)氨基]-2-吡啶基]氨基]苯甲酰胺 | 1206170-62-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-[[4-氨基-5-氰基-6-[(1,1-二甲基乙基)氨基]-2-吡啶基]氨基]苯甲酰胺
• 英文名称: 4-[[4-amino-6-(tert-butylamino)-5-cyano-2-pyridyl]amino]benzamide
• 英文别名: 4-(4-amino-6-(tert-butylamino)-5-cyanopyridin-2-ylamino)benzamide；TC-Mps1-12；4-[[4-amino-6-(tert-butylamino)-5-cyanopyridin-2-yl]amino]benzamide
• CAS: 1206170-62-8
• 化学式: C₁₇H₂₀N₆O
• 分子量: 324.385
• InChiKey: XDEFNAWAKYQBQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  130
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4,6-二氨基-2-溴烟腈 在 氨 、 palladium diacetate 、 caesium carbonate 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium hydroxide 作用下， 以 N-甲基吡咯烷酮 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.25h， 生成 4-[[4-氨基-5-氰基-6-[(1,1-二甲基乙基)氨基]-2-吡啶基]氨基]苯甲酰胺
  参考文献：
  名称：

  Diaminopyridine-Based Potent and Selective Mps1 Kinase Inhibitors Binding to an Unusual Flipped-Peptide Conformation

  摘要：

  Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

  DOI：

  10.1021/ml3000879

文献信息

• [EN] PROGNOSTIC BIOMARKERS FOR TTK INHIBITOR CHEMOTHERAPY<br/>[FR] BIOMARQUEURS PRONOSTIQUES POUR CHIMIOTHÉRAPIE BASÉE SUR UN INHIBITEUR DE TTK
  申请人：NETHERLANDS TRANSLATIONAL RES CENTER B V

  公开号：WO2016166255A1

  公开（公告）日：2016-10-20

  The present invention provides a method for identifying a tumor - in a human individual or in an animal - that is susceptible to treatment with a TTK inhibitor, said method comprising: a] providing a sample of a tumor; b] determining the presence of a mutated CTNNB1 gene in said tumor sample, wherein said mutation is located in exon 3 of CTNNB1 and whereby the presence of a mutated CTNNB1 gene indicates that the tumor is susceptible to treatment with a TTK inhibitor. In an alternative aspect, step b] of the above defined method is replaced by the step of determining the presence of a mutated CTNNB1 protein in said tumor sample, wherein said mutation is located in exon 3 of CTNNB1 and whereby the presence of a mutated CTNNB1 protein indicates that the tumor is susceptible to treatment with a TTK inhibitor. In a further alternative, step b] comprises determining an altered expression of a CTNNB1 regulated gene, whereby an altered expression of a CTNNB1 regulated gene indicates that the tumor is susceptible to treatment with a TTK inhibitor.

  本发明提供了一种用于识别易受TTK抑制剂治疗的人体或动物肿瘤的方法，所述方法包括：a] 提供肿瘤样本；b] 确定肿瘤样本中是否存在突变的CTNNB1基因，其中所述突变位于CTNNB1的第3外显子中，并且存在突变的CTNNB1基因表明肿瘤易受TTK抑制剂治疗。在另一种方面，上述定义方法的步骤b] 被替换为确定肿瘤样本中是否存在突变的CTNNB1蛋白，其中所述突变位于CTNNB1的第3外显子中，并且存在突变的CTNNB1蛋白表明肿瘤易受TTK抑制剂治疗。在进一步的替代方案中，步骤b] 包括确定CTNNB1调控基因的表达改变，其中CTNNB1调控基因的表达改变表明肿瘤易受TTK抑制剂治疗。
• Prognostic biomarkers for TTK inhibitor chemotherapy
  申请人：NETHERLANDS TRANSLATIONAL RESEARCH CENTER B.V.

  公开号：US11208696B2

  公开（公告）日：2021-12-28

  A method for identifying a tumor that is susceptible to treatment with a TTK inhibitor, including: a) providing a sample of a tumor; b) determining the presence of a mutated CTNNB1 gene in the sample, wherein the mutation is located in exon 3 of CTNNB1 and the presence of a mutated CTNNB1 gene indicates the tumor is susceptible to treatment with a TTK inhibitor. Alternatively, step b) is replaced by the step of determining the presence of a mutated CTNNB1 protein in the sample, wherein the mutation is located in exon 3 of CTNNB1 and the presence of a mutated CTNNB1 protein indicates the tumor is susceptible to treatment with a TTK inhibitor. In a further alternative, step b) includes determining an altered expression of a CTNNB1 regulated gene, whereby an altered expression of a CTNNB1 regulated gene indicates the tumor is susceptible to treatment with a TTK inhibitor.

  一种鉴定易受TTK抑制剂治疗的肿瘤的方法，包括：a)提供肿瘤样本；b)确定样本中是否存在突变的CTNNB1基因，其中突变位于CTNNB1的第3外显子，突变的CTNNB1基因的存在表明肿瘤易受TTK抑制剂的治疗。或者，将步骤 b) 替换为确定样本中是否存在突变的 CTNNB1 蛋白，其中突变位于 CTNNB1 的第 3 号外显子，且突变的 CTNNB1 蛋白的存在表明肿瘤易受 TTK 抑制剂的治疗。在另一种选择中，步骤 b) 包括确定 CTNNB1 受控基因表达的改变，其中 CTNNB1 受控基因表达的改变表明肿瘤易受 TTK 抑制剂的治疗。
• PROGNOSTIC BIOMARKERS FOR TTK INHIBITOR CHEMOTHERAPY
  申请人：Netherlands Translational Research Center B.V.

  公开号：EP3283642A1

  公开（公告）日：2018-02-21
• MEDICAL USES AND METHODS FOR TREATING CANCER USING MONOPOLAR SPINDLE 1 (MPS1) KINASE INHIBITORS
  申请人：THE INSTITUTE OF CANCER RESEARCH: ROYAL CANCER HOSPITAL

  公开号：US20180112258A1

  公开（公告）日：2018-04-26

  Medical uses and methods are provided for treating cancer using monopolar spindle 1 (MPS1) kinase inhibitors. Methods and uses for selecting MPS1 kinase inhibitors for use in treating cancer in a subject are provided, both in the initial selection of MPS1 kinase inhibitors and for addressing the development of acquired drug resistance that occur in the course of treatment.
• METHODS OF TREATING CANCERS CHARACTERIZED BY A HIGH EXPRESSION LEVEL OF SPINDLE AND KINETOCHORE ASSOCIATED COMPLEX SUBUNIT 3 (SKA3) GENE
  申请人：UNIVERSITY HEALTH NETWORK

  公开号：US20210290624A1

  公开（公告）日：2021-09-23

  Provided herein are methods of treating cancers characterized by a high expression of SKA3 gene, such as: breast cancer, prostate cancer, endometrial cancer, ovarian cancer, brain cancer, skin cancer, thyroid cancer, lung cancer, mesothelioma cancer, bladder cancer, colorectal cancer, liver cancer, melanoma, glioblastoma, leukemia or lymphoma, comprising administering a therapeutically effective amount of a TTK inhibitor, such as: CFI-402257, BAY 1161909, BAY 1217389, AZ-3146, NMS-P715, TC Mps1 12, reversine, Mps1-IN-1, Mps1-IN-2, Mps1-IN-3, MPS BAY1, MPS BAY2a, MPS BAY2b, MPI-0479605, SP600125, S81694/NMS-P153; BOS172722; NTRC 0060-0; NTRC 1501-0; and a pharmaceutically acceptable salt thereof.