p53-MDM2 inhibitor MCL0527-3 | 1383627-56-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: p53-MDM2 inhibitor MCL0527-3
• 英文别名: 2-amino-4,5-bis(4-chlorophenyl)-N-cyclohexylthiophene-3-carboxamide
• CAS: 1383627-56-2
• 化学式: C₂₃H₂₂Cl₂N₂OS
• 分子量: 445.412
• InChiKey: RLUGRMMSGGKTPV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  83.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  p53-MDM2 inhibitor MCL0527-3 在 劳森试剂 作用下， 以 甲苯 为溶剂， 反应 1.0h， 以35%的产率得到2-amino-4,5-bis(4-chlorophenyl)-N-cyclohexylthiophene-3-carbothioamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53–MDM2 interaction. Part 2

  摘要：

  Five series of novel 3,4,5-trisubstituted aminothiophene derivatives and analogs were designed and synthesized based on our previous studies. All target compounds were evaluated for their p53-MDM2 binding inhibitory activities and anti-proliferation activities against A549 and PC3 tumor cell lines. Twelve compounds displayed comparable p53-MDM2 binding inhibitory activities to that of Nutlin-3. Among them, compound 7a exhibited marked binding affinity (IC50 = 0.086 mu M). In addition, most target compounds showed potent anti-proliferation activities with IC50 values at low micromolar level. A good selective profile for wild-type p53 expression cell line was also observed. Molecular docking analysis was performed as well to predict possible binding modes of target compounds with MDM2. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.070
• 作为产物：
  描述：

  2,4'-二氯苯乙酮 在 吡啶 、 aluminum (III) chloride 、 四氯化钛 、 sulfur 、 二乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 p53-MDM2 inhibitor MCL0527-3
  参考文献：
  名称：

  Identification of novel inhibitors of p53–MDM2 interaction facilitated by pharmacophore-based virtual screening combining molecular docking strategy

  摘要：

  针对p53-MDM2相互作用抑制剂的3D药效团模型已被开发出来。通过基于药效团的自家化合物数据库虚拟筛选与对接研究相结合，鉴定出了化合物MCL0527作为一种新型先导化合物（MDM2结合IC50 = 4.23 μM）。初步的结构优化获得了一些衍生物，它们具有更优的p53-MDM2结合抑制活性。此外，所有目标化合物均显示出对携带野生型p53的人类肿瘤细胞系具有强力的抗增殖效应，并表现出一般的选择性特征。

  DOI：

  10.1039/c2md20208e

文献信息

• [EN] HETERO-BIFUNCTIONAL DEGRADER COMPOUNDS AND THEIR USE AS MODULATORS OF TARGETED UBIQUINATION (VHL)<br/>[FR] COMPOSÉS DE DÉGRADATION HÉTÉRO-BIFONCTIONNELS ET LEUR UTILISATION EN TANT QUE MODULATEURS DE L'UBIQUINATION CIBLÉE (VHL)
  申请人：GENENTECH INC

  公开号：WO2019183523A1

  公开（公告）日：2019-09-26

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds that contain on one end a VHL ligand moiety, which binds to the VHL ubiquitin ligase (E3), and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. The target protein may be EGFR. Also disclosed are VHL ligands.

  本公开涉及双功能化合物，可用作靶向泛素化的调节剂。特别是，本公开是针对包含在一端具有VHL配体基团的化合物，该基团结合到VHL泛素连接酶(E3)，而在另一端具有结合目标蛋白的基团，从而实现目标蛋白/多肽的降解。目标蛋白可以是EGFR。还公开了VHL配体。
• (4-hydroxypyrrolidin-2-yl)-heterocyclic compounds and methods of use thereof
  申请人：Genentech, Inc.

  公开号：US11242344B2

  公开（公告）日：2022-02-08

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands.

  本公开涉及可用作靶向泛素化调节剂的双功能化合物。特别是，本公开涉及的化合物一端含有与 VHL E3 泛素连接酶结合的 VHL 配体分子，另一端含有与靶蛋白结合的分子，从而实现靶蛋白/多肽的降解。还公开了 VHL 配体。
• (4-HYDROXYPYRROLIDIN-2-YL)-HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
  申请人：Genentech, Inc.

  公开号：US20210309660A1

  公开（公告）日：2021-10-07

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands.
• Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53–MDM2 interaction. Part 2
  作者：Weisi Wang、Dan Lv、Ni Qiu、Lei Zhang、Chunqi Hu、Yongzhou Hu

  DOI：10.1016/j.bmc.2013.03.070

  日期：2013.6

  Five series of novel 3,4,5-trisubstituted aminothiophene derivatives and analogs were designed and synthesized based on our previous studies. All target compounds were evaluated for their p53-MDM2 binding inhibitory activities and anti-proliferation activities against A549 and PC3 tumor cell lines. Twelve compounds displayed comparable p53-MDM2 binding inhibitory activities to that of Nutlin-3. Among them, compound 7a exhibited marked binding affinity (IC50 = 0.086 mu M). In addition, most target compounds showed potent anti-proliferation activities with IC50 values at low micromolar level. A good selective profile for wild-type p53 expression cell line was also observed. Molecular docking analysis was performed as well to predict possible binding modes of target compounds with MDM2. (C) 2013 Elsevier Ltd. All rights reserved.
• Identification of novel inhibitors of p53–MDM2 interaction facilitated by pharmacophore-based virtual screening combining molecular docking strategy
  作者：Weisi Wang、Xiaolei Zhu、Xueqin Hong、Lin Zheng、Hong Zhu、Yongzhou Hu

  DOI：10.1039/c2md20208e

  日期：——

  3D pharmacophore models for inhibitors of p53–MDM2 interaction were developed. The pharmacophore-based virtual screening of an in-house compound database combined with docking studies led to the identification of compound MCL0527 as a novel lead (MDM2 binding IC50 = 4.23 μM). Initial structure optimization yielded some derivatives with improved p53–MDM2 binding inhibitory activities. Furthermore, all target compounds showed potent anti-proliferative effect against human tumor cell lines with a generally selective profile on wild-type p53 cell lines.

  针对p53-MDM2相互作用抑制剂的3D药效团模型已被开发出来。通过基于药效团的自家化合物数据库虚拟筛选与对接研究相结合，鉴定出了化合物MCL0527作为一种新型先导化合物（MDM2结合IC50 = 4.23 μM）。初步的结构优化获得了一些衍生物，它们具有更优的p53-MDM2结合抑制活性。此外，所有目标化合物均显示出对携带野生型p53的人类肿瘤细胞系具有强力的抗增殖效应，并表现出一般的选择性特征。