PK5196 | 1370554-91-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: PK5196
• 英文别名: 2-{[4-(Diethylamino)piperidin-1-Yl]methyl}-6-Iodo-4-[3-(Phenylamino)prop-1-Yn-1-Yl]phenol；4-(3-anilinoprop-1-ynyl)-2-[[4-(diethylamino)piperidin-1-yl]methyl]-6-iodophenol
• CAS: 1370554-91-8
• 化学式: C₂₅H₃₂IN₃O
• 分子量: 517.453
• InChiKey: IZUZDXSTWPMHFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  38.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  N-(2-丙炔基)苯胺 、 2-{[4-(diethylamino)piperidin-1-yl]methyl}-4,6-diiodophenol 在 Pd⁰/Cu^I 作用下， 生成 PK5196
  参考文献：
  名称：

  Halogen-Enriched Fragment Libraries as Leads for Drug Rescue of Mutant p53

  摘要：

  The destabilizing p53 cancer mutation Y220C creates a druggable surface crevice. We developed a strategy exploiting halogen bonding for lead discovery to stabilize the mutant with small molecules. We designed halogen-enriched fragment libraries (HEFLibs) as starting points to complement classical approaches. From screening of HEFLibs and subsequent structure-guided design, we developed substituted 2-(aminomethyl)-4-ethynyl-6-iodophenols as p53-Y220C stabilizers. Crystal structures of their complexes highlight two key features: (i) a central scaffold with a robust binding mode anchored by halogen bonding of an iodine with a main-chain carbonyl and (ii) an acetylene linker, enabling the targeting of an additional subsite in the crevice. The best binders showed induction of apoptosis in a human cancer cell line with homozygous Y220C mutation. Our structural and biophysical data suggest a more widespread applicability of HEFLibs in drug discovery.

  DOI：

  10.1021/ja301056a

文献信息

• [EN] P53 MODULATORS AND USES THEREOF<br/>[FR] MODULATEURS DE p53 ET UTILISATIONS DE CEUX-CI
  申请人：UNIV CALIFORNIA

  公开号：WO2021087096A1

  公开（公告）日：2021-05-06

  Described herein, inter alia, are p53 modulator compounds and methods of using the same. In an aspect is provided a p53 protein covalently bonded to a compound described herein. In an aspect is provided a pharmaceutical composition including a compound described herein and a pharmaceutically acceptable excipient. In an aspect is provided a method of treating cancer in a subject in need of such treatment, including administering to the subject an effective amount of a compound described herein.

  本文描述了p53调节剂化合物及其使用方法等内容。在一个方面，提供了一种p53蛋白与本文描述的化合物共价结合的方法。在一个方面，提供了一种包含本文描述的化合物和药用辅料的药物组合物。在一个方面，提供了一种治疗需要此类治疗的受试者的癌症的方法，包括向受试者施用本文描述的化合物的有效量。
• METHODS FOR DETECTING MUTANT P53 FUNCTION
  申请人：PMV Pharmaceuticals, Inc.

  公开号：US20210405056A1

  公开（公告）日：2021-12-30

  Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The methods described herein can detect and quantify the ability of a therapeutic agent to reconform a mutant conformation of mutant p53 to a conformation that possesses physiological activity of wild type p53. The disclosed method can be used as a companion diagnostic to detect and quantify the efficacy of a therapeutic agent in reducing the progression of cancers that contain a p53 mutation.
• Halogen-Enriched Fragment Libraries as Leads for Drug Rescue of Mutant p53
  作者：Rainer Wilcken、Xiangrui Liu、Markus O. Zimmermann、Trevor J. Rutherford、Alan R. Fersht、Andreas C. Joerger、Frank M. Boeckler

  DOI：10.1021/ja301056a

  日期：2012.4.18

  The destabilizing p53 cancer mutation Y220C creates a druggable surface crevice. We developed a strategy exploiting halogen bonding for lead discovery to stabilize the mutant with small molecules. We designed halogen-enriched fragment libraries (HEFLibs) as starting points to complement classical approaches. From screening of HEFLibs and subsequent structure-guided design, we developed substituted 2-(aminomethyl)-4-ethynyl-6-iodophenols as p53-Y220C stabilizers. Crystal structures of their complexes highlight two key features: (i) a central scaffold with a robust binding mode anchored by halogen bonding of an iodine with a main-chain carbonyl and (ii) an acetylene linker, enabling the targeting of an additional subsite in the crevice. The best binders showed induction of apoptosis in a human cancer cell line with homozygous Y220C mutation. Our structural and biophysical data suggest a more widespread applicability of HEFLibs in drug discovery.