AP24534 | 1232836-26-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: AP24534
• 英文别名: N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methylbenzamide；N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide
• CAS: 1232836-26-8
• 化学式: C₃₀H₂₉F₃N₆O
• 分子量: 546.595
• InChiKey: CPODEIRRQNWWDX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  40
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  65.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-乙炔咪唑并[1,2-b]吡嗪 、 N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-iodo-4-methyl-benzamide 在 copper(l) iodide 、 四(三苯基膦)钯 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 AP24534
  参考文献：
  名称：

  Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant

  摘要：

  In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of I1e315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CM L, including patients refractory to all currently approved therapies.

  DOI：

  10.1021/jm100395q

文献信息

• DDR2 mutations in squamous cell lung cancer
  申请人：The Broad Institute, Inc.

  公开号：US10385403B2

  公开（公告）日：2019-08-20

  Methods for treating patients with squamous cell lung cancer, including detecting the presence of mutations in the discoidin domain receptor 2 (DDR2) gene.

  治疗鳞状细胞肺癌患者的方法，包括检测是否存在盘状结构域受体 2 (DDR2) 基因突变。
• Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10925868B2

  公开（公告）日：2021-02-23

  The present application provides bifunctional compounds of Formula (I): or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases (e.g., Bcr-Abl). The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.

  本申请提供了式 (I) 的双官能化合物： 或其对映体、非对映体或立体异构体，或其药学上可接受的盐、水合物、溶液或原药，它们可作为蛋白激酶（如 Bcr-Abl）的蛋白降解诱导分子。本申请还涉及通过使用双功能化合物靶向降解一种或多种蛋白激酶的方法，该双功能化合物将泛素连接酶结合分子与能够与一种或多种蛋白激酶结合的配体连接起来，可用于治疗受蛋白激酶调节的疾病。
• DDR2 Mutations in Squamous Cell Lung Cancer
  申请人：THE BROAD INSTITUTE, INC.

  公开号：US20130261017A1

  公开（公告）日：2013-10-03

  Methods for treating patients with squamous cell lung cancer, including detecting the presence of mutations in the discoidin domain receptor 2 (DDR2) gene.
• US9499856B2
  申请人：——

  公开号：US9499856B2

  公开（公告）日：2016-11-22
• [EN] CRYSTALLINE FORMS OF 3-(IMIDAZO[1,2-B] PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-(4-[(4-METHYLPIPERAZIN-1-YL) METHYL]-3-(TRIFLUOROMETHYL)PHENYL)BENZAMIDE AND ITS MONO HYDROCHLORIDE SALT<br/>[FR] FORMES CRISTALLINES DE 3-(IMIDAZO[1,2-B]PYRIDAZIN-3-YLÉTHYNYL)-4-MÉTHYL-N-(4-[(4-MÉTHYLPIPÉRAZIN-1-YL)MÉTHYL]-3-(TRIFLUOROMÉTHYL)PHÉNYL)BENZAMIDE ET DE SON SEL MONOCHLORHYDRATE
  申请人：ARIAD PHARMA INC

  公开号：WO2014093579A2

  公开（公告）日：2014-06-19

  Novel crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-4-[(4- methylpiperazin-1 -yl)methyl]-3-(trifluoromethyl)phenyl}benzamide free base and 3-(imidazo[1,2- b]pyridazin-3-ylethynyl)-4-methyl-N-4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl}benzamide mono hydrochloride, pharmaceutical compositions thereof and methods of their preparation and use are disclosed herein.