1-((2S)-2-((N-(tert-butoxycarbonyl)-N-methyl-L-alanyl)amino)-2-cyclohexylacetyl)-L-prolyl-β-phenyl-L-phenylalanine | 1384275-60-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 1-((2S)-2-((N-(tert-butoxycarbonyl)-N-methyl-L-alanyl)amino)-2-cyclohexylacetyl)-L-prolyl-β-phenyl-L-phenylalanine
• 英文别名: (S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidin-2-carboxamido)-3,3-diphenylpropanoic acid；(S)-2-((S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanoic acid；Boc-N(Me)Ala-Chg-Pro-Dip-OH；(2S)-2-[[(2S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-3,3-diphenylpropanoic acid
• CAS: 1384275-60-8
• 化学式: C₃₇H₅₀N₄O₇
• 分子量: 662.827
• InChiKey: CAARRLWPQNHLNA-UIMLXMIHSA-N

物化性质

• 沸点：
  872.6±65.0 °C(Predicted)
• 密度：
  1.205±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  48
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-((2S)-2-((N-(tert-butoxycarbonyl)-N-methyl-L-alanyl)amino)-2-cyclohexylacetyl)-L-prolyl-β-phenyl-L-phenylalanine 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 3.5h， 以87%的产率得到
  参考文献：
  名称：

  Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist

  摘要：

  Protein knockdown can be achieved by the use of a small molecule that possesses affinity for both the target protein and ubiquitin ligase. We have designed such a degradation-inducing molecule targeting cIAP1 and CRABP-II, which are involved in proliferation of several cancer cell lines and in neuroblastoma growth, respectively. As a CRABP-II-recognizing moiety, all-trans retinoic acid ( ATRA, 3), a physiological ligand of CRABP, was chosen. As a cIAP1-recognizing moiety, MV1 ( 5), which is a cIAP1/cIAP2/XIAP panligand, was chosen. Although cIAP1 itself possesses ubiquitin ligase activity, we expected that its decomposition would be efficiently mediated by related molecules, including cIAP2 and XIAP, which also possess ubiquitin ligase activity. The designed degradation inducer 6, in which ATRA ( 3) and MV1 ( 5) moieties are connected via a linker, was synthesized and confirmed to induce efficient degradation of both cIAP1 and CRABP-II. It showed potently inhibited the proliferation of IMR32 cells. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.04.134
• 作为产物：
  描述：

  benzyl 1-((2S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-L-prolyl-β-phenyl-L-phenylalaninate 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 1-((2S)-2-((N-(tert-butoxycarbonyl)-N-methyl-L-alanyl)amino)-2-cyclohexylacetyl)-L-prolyl-β-phenyl-L-phenylalanine
  参考文献：
  名称：

  雄激素受体配体与凋亡蛋白配体抑制剂的结合开发雄激素受体蛋白降解诱导剂

  摘要：

  使用小分子进行有针对性的蛋白质降解是药物开发的新策略。我们已经开发了杂交分子，命名为凋亡蛋白[IAP]依赖蛋白橡皮擦（SNIPERs）的特异性和非遗传抑制剂，这些蛋白可以募集IAP泛素连接酶来降解目标蛋白。在这里，我们显示了新型的SNIPERs，能够诱导雄激素受体（AR）的蛋白酶体降解。通过在AR配体和IAP配体和接头处SNIPER（AR）分子的衍生化，我们开发了42a（SNIPER（AR）-51），该蛋白显示出针对AR的有效蛋白敲低活性。与AR蛋白的降解一致，42a抑制AR介导的基因表达和雄激素依赖性前列腺癌细胞的增殖。另外42a有效诱导前列腺癌细胞中的半胱天冬酶激活和凋亡，这在用AR拮抗剂处理的细胞中未观察到。这些结果表明，SNIPER（AR）可能是抗前列腺癌抗癌药物的先导，而前列腺癌表现出AR依赖性增殖。

  DOI：

  10.1021/acs.jmedchem.7b00168

文献信息

• [EN] BI-FUNCTIONAL COMPOUNDS AND METHODS FOR TARGETED UBIQUITINATION OF ANDROGEN RECEPTOR<br/>[FR] COMPOSÉS BI-FONCTIONNELS ET PROCÉDÉS D'UBIQUITINATION CIBLÉE DU RÉCEPTEUR DES ANDROGÈNES
  申请人：MONTELINO THERAPEUTICS INC

  公开号：WO2021236695A1

  公开（公告）日：2021-11-25

  The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.

  本发明涉及具有双重功能的化合物，其功能是招募内源蛋白质到E3泛素连接酶进行降解，并使用相同的方法。更具体地，本公开提供了特定的蛋白质降解靶向嵌合物（PROTAC）分子，这些分子作为调节各种多肽和其他蛋白质的靶向泛素化的调节剂，特别是缺乏LBD的AR的一个切片变体的雄激素受体，标记为AR-V7，然后通过所述化合物进行降解和/或其他方式被抑制。
• BI-FUNCTIONAL COMPOUNDS AND METHODS FOR TARGETED UBIQUITINATION OF ANDROGEN RECEPTOR
  申请人：MONTELINO THERAPEUTICS, LLC

  公开号：US20200239430A1

  公开（公告）日：2020-07-30

  The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.

  本发明涉及具有双重功能的化合物，其功能是招募内源蛋白质到E3泛素连接酶进行降解，并使用相同的方法。更具体地，本公开提供了特定的蛋白酶靶向融合物（PROTAC）分子，这些分子作为调节各种多肽和其他蛋白质的靶向泛素化的调节剂，特别是缺乏LBD的AR的一个切片变体的雄激素受体，标记为AR-V7，然后通过所述化合物进行降解和/或其他方式抑制。
• Design and synthesis of peptide-based chimeric molecules to induce degradation of the estrogen and androgen receptors
  作者：Hidetomo Yokoo、Nobumichi Ohoka、Mikihiko Naito、Yosuke Demizu

  DOI：10.1016/j.bmc.2020.115595

  日期：2020.8

  Peptide-based inducers of estrogen receptor (ER) α and androgen receptor (AR) degradations via the ubiquitin–proteasome system (UPS) were developed. The designated inducers were composed of two biologically active scaffolds: the helical peptide PERM3, which is an LXXLL-like mimic of the coactivator SRC-1, and various small molecules (MV1, LCL161, VH032, and POM) that bind to E3 ligases (IAPs, VHL,

  开发了通过泛素-蛋白酶体系统 (UPS) 降解雌激素受体 (ER) α 和雄激素受体 (AR) 的肽基诱导剂。指定的诱导剂由两个生物活性支架组成：螺旋肽PERM3，它是共激活剂 SRC-1 的 LXXLL 样模拟物，以及与 E3 连接酶结合的各种小分子（MV1、LCL161、VH032 和 POM）。 IAP、VHL 和 cereblon），以诱导与 SRC-1 结合的核受体的泛素化。所有合成的含有嵌合 E3 配体的分子都诱导了 UPS 介导的 ERα 和 AR 降解。该PERM3肽是适用于使用这些E3配体ERα和AR降解菌的发展。
• Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand
  作者：Shusuke Tomoshige、Yuichi Hashimoto、Minoru Ishikawa

  DOI：10.1016/j.bmc.2016.05.035

  日期：2016.7

  of alkyl chloride, which binds covalently to HaloTag, linked to BE04 (2), a bestatin (3) derivative with an affinity for cellular inhibitor of apoptosis protein 1 (cIAP1, a kind of ubiquitin ligase). This system addressed several limitations of prior protein knockdown technology, and was applied to degrade two HaloTag-fused proteins. However, the degradation activity of these hybrid small molecules

  我们先前曾报道过HaloTag融合蛋白的蛋白敲低系统，该蛋白使用由烷基氯组成的杂化小分子，该分子与HaloTag共价结合，并与BE04（2），与细胞凋亡蛋白1的细胞抑制剂具有亲和力的Bestatin（3）衍生物连接。 （cIAP1，一种泛素连接酶）。该系统解决了现有蛋白敲低技术的几个局限性，并被用于降解两种HaloTag融合蛋白。但是，这些杂化小分子的降解活性不强。因此，我们着手改进此系统。我们在这里报告了由IAP拮抗剂MV1连接的烷基氯化物组成的新型杂化化合物4a和4b的设计，合成和生物学评估（5）。证实化合物4a和4b可以比BE04更有效地降低活细胞中HaloTag融合的肿瘤坏死因子α（HaloTag-TNFα），HaloTag融合的细胞分裂控制蛋白42（HaloTag-Cdc42）和未融合的HaloTag蛋白的水平。 -连接的化合物1b。作用方式的分析表明，HaloTag-TNFα的
• Development of a Small Hybrid Molecule That Mediates Degradation of His-Tag Fused Proteins
  作者：Koyo Okitsu、Takayuki Hattori、Takashi Misawa、Takuji Shoda、Masaaki Kurihara、Mikihiko Naito、Yosuke Demizu

  DOI：10.1021/acs.jmedchem.7b00413

  日期：2018.1.25

  In recent years, the induction of target-protein degradation via the ubiquitin-proteasome system (UPS) mediated by small molecules has attracted attention, and this approach has applications in pharmaceutical development. However, this technique requires a ligand for the target protein that can be incorporated into tailor-made molecules, and there are many proteins for which such ligands have not been found. In this study, we developed a protein-knockdown method that recognizes a His-tag fused to a protein of interest. This strategy theoretically allows comprehensive targeting of proteins of interest by a particular molecule recognizing the tag. As expected, our hybrid molecule 10 [SNIPER(CH6)] efficiently degraded His-tagged CRABP-II and Smad2 in cells. This system provides an easy method to determine the susceptibility of proteins of interest to UPS-mediated degradation. Furthermore, we hope that this method will become an efficient tool to analyze the function of the UPS.