1-[4-[[4-[[2-(异丙基磺酰基)苯基]氨基]-1H-吡咯并[2,3-B]吡啶-6-基]氨基]-3-甲氧基苯基]哌啶-4-醇 | 1125593-20-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 1-[4-[[4-[[2-(异丙基磺酰基)苯基]氨基]-1H-吡咯并[2,3-B]吡啶-6-基]氨基]-3-甲氧基苯基]哌啶-4-醇
• 英文名称: 1-(4-(4-(2-(Isopropylsulfonyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-3-methoxyphenyl)piperidin-4-ol
• 英文别名: 1-[3-methoxy-4-[[4-(2-propan-2-ylsulfonylanilino)-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]phenyl]piperidin-4-ol
• CAS: 1125593-20-5
• 化学式: C₂₈H₃₃N₅O₄S
• 分子量: 535.7
• InChiKey: NMJMRSQTDLRCRQ-UHFFFAOYSA-N

物化性质

• 密度：
  1.354±0.06 g/cm3(Predicted)
• 溶解度：
  不溶于水； DMSO 中≥16.05 mg/mL；乙醇中≥9.26 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  128
• 氢给体数：
  4
• 氢受体数：
  8

制备方法与用途

生物活性

Mps1-IN-1 是一种有效的、选择性的、ATP 竞争性的 Mps1 抑制剂，其 IC50 和 Kd 值分别为 367 nM 和 27 nM。此外，它还对 ALK 和 LTK 具有高亲和力，Kd 值分别为 21 nM 和 29 nM。然而，它在其他 352 种激酶中的抑制作用较小或几乎无抑制作用。

靶点

• Mps1: IC50 = 367 nM
• Mps1: Kd = 27 nM
• ALK: Kd = 21 nM
• LTK: Kd = 29 nM
• PYK2: Kd = 280 nM
• FAK: Kd = 440 nM
• IGF1R: Kd = 750 nM
• INSR: Kd = 470 nM
• CLK1: Kd = 1900 nM
• ERK2: Kd = 2900 nM
• INSRR: Kd = 1200 nM
• TNK1: Kd = 2600 nM
• TNK2: Kd = 3100 nM
• GAK: Kd = 1100 nM

体外研究

Mps1-IN-1 是一种强效、选择性且 ATP 竞争性的 Mps1 蛋白激酶抑制剂，其 IC50 和 Kd 值分别为 367 nM 和 27 nM。此外，它还对 ALK 和 LTK 具有高亲和力，Kd 分别为 21 nM 和 29 nM。

• Mps1-IN-1（5、10 μM）可在 U2OS 细胞中诱导克服由检查点介导的有丝分裂停滞。
• Mps1-IN-1 干扰 Mad2 向染色体凝集素的招募，并减少 Aurora B 在 Thr232 位点的磷酸化状态。
• Mps1-IN-1（10 μM）对中心粒复制无明显影响。
• 此外，Mps1-IN-1（5-10 μM）抑制 HCT116 的增殖能力。

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
• 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.
• [EN] AMINO SUBSTITUTED PYRIMIDINE, PYROLLOPYRIDINE AND PYRAZOLOPYRIMIDINE DERIVATIVES USEFUL AS KINASE INHIBITORS AND IN TREATING PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS<br/>[FR] PYRIMIDINE SUBSTITUÉE PAR AMINO, DÉRIVÉS DE PYROLLOPYRIDINE ET DE PYRAZOLOPYRIMIDINE UTILISÉS EN TANT QU'INHIBITEURS DE LA KINASE ET DANS LE TRAITEMENT DE TROUBLES PROLIFÉRATIFS ET DE MALADIES LIÉES À L'ANGIOGENÈSE
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2009032694A1

  公开（公告）日：2009-03-12

  This invention relates to novel amino subsituted pyrimidine compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.