SM 406; (5S,8S,10aR)-N-(二苯基甲基)十氢-5-[[(2S)-2-(甲基氨基)-1-氧代丙基]氨基]-3-(3-甲基-1-氧代丁基)-6-氧代吡咯并[1,2-a][1,5]二氮杂环辛烷-8-甲酰胺 | 1071992-99-8

• 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
• 中文名称: SM 406; (5S,8S,10aR)-N-(二苯基甲基)十氢-5-[[(2S)-2-(甲基氨基)-1-氧代丙基]氨基]-3-(3-甲基-1-氧代丁基)-6-氧代吡咯并[1,2-a][1,5]二氮杂环辛烷-8-甲酰胺
• 中文别名: SM406;(5S,8S,10aR)-N-(二苯基甲基)十氢-5-[[(2S)-2-(甲基氨基)-1-氧代丙基]氨基]-3-(3-甲基-1-氧代丁基)-6-氧代吡咯并[1,2-a][1,5]二氮杂环辛烷-8-甲酰胺
• 英文名称: (5S,8S,10aR)-N-benzhydryl-5-((S)-2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
• 英文别名: Debio 1143；AT406；AT-406；SM-406；Xevinapant；(5S,8S,10aR)-N-benzhydryl-5-[[(2S)-2-(methylamino)propanoyl]amino]-3-(3-methylbutanoyl)-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
• CAS: 1071992-99-8
• 化学式: C₃₂H₄₃N₅O₄
• 分子量: 561.725
• InChiKey: LSXUTRRVVSPWDZ-MKKUMYSQSA-N

物化性质

• 沸点：
  840.6±65.0 °C(Predicted)
• 密度：
  1.21
• 溶解度：
  DMSO 中≥27.65 mg/mL；不溶于水；乙醇中≥27 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  41
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20℃

制备方法与用途

生物活性

Xevinapant (AT406, ARRY-334543, Debio1143, SM-406) 是一种有效的拟Smac的IAP(通过E3泛素连接酶起作用的凋亡蛋白抑制剂)拮抗剂，能与XIAP-BIR3、cIAP1-BIR3和cIAP2-BIR3结合，Ki值分别为66.4 nM、1.9 nM和5.1 nM。它对Smac AVPI肽的亲和力比作用于Smac AVPI肽高50到100倍。

靶点

Target	Value
cIAP1-BIR3 (细胞外实验)	1.9 nM(Ki)
cIAP2-BIR3 (细胞外实验)	5.1 nM(Ki)
XIAP-BIR3 (细胞外实验)	66.4 nM(Ki)

体外研究

AT-406是一种Smac模拟物，在氢键结合和与XIAP的疏水性相互作用中，能够很好地模拟AVPI多肽，并伴随额外的W323位点疏水性接触。与Smac AVPI多肽相比，它对这些IAPs具有50-100倍的结合亲和力。

AT-406 (1 μM) 完全恢复了在无细胞体系中被500 nM XIAP BIR3抑制的caspase-9活性。在MDA-MB-231细胞中，它诱导了快速的cIAP1降解，并摧毁了细胞XIAP蛋白。AT-406有效抑制了大量人癌症细胞系，在MDA-MB-231细胞和SK-OV-3卵巢癌细胞中的IC50分别为144 nM和142 nM，对正常的人乳腺样上皮MCF-12F细胞和初级人正常前列腺上皮细胞具有低毒性。在MDA-MB-231细胞中，AT-406通过诱导caspase-3活化和PARP裂解，促进了细胞凋亡。

体内研究

AT-406 在小鼠、大鼠、非灵长类动物及狗体内的药代动力学(PK)性能和口服生物利用度良好。在MDA-MB-231异种移植物中，它有效诱导了肿瘤组织中cIAP1的降解以及半胱天冬酶-8的加工，PARP的裂解，在100 mg/kg甚至200 mg/kg剂量下表现出良好的耐受性。AT-406诱导了显著的肿瘤生长抑制，在100 mg/kg剂量下P值为0.0012。

文献信息

• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES
  申请人：Arvinas, Inc.

  公开号：US20190151295A1

  公开（公告）日：2019-05-23

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为白细胞介素-1受体相关激酶4（IRAK-4；目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合E3泛素连接酶的Von Hppel-Lindau、cereblon配体的双功能化合物，另一端结合目标蛋白的部分，使得目标蛋白靠近泛素连接酶以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。
• [EN] PROTEOLYSIS TARGETING CHIMERIC (PROTAC) COMPOUND WITH E3 UBIQUITIN LIGASE BINDING ACTIVITY AND TARGETING ALPHA-SYNUCLEIN PROTEIN FOR TREATING NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉ CHIMÈRE CIBLANT LA PROTÉOLYSE (PROTAC) AYANT UNE ACTIVITÉ DE LIAISON À L'UBIQUITINE LIGASE E3 ET CIBLANT UNE PROTÉINE ALPHA-SYNUCLÉINE POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
  申请人：ARVINAS OPERATIONS INC

  公开号：WO2020041331A1

  公开（公告）日：2020-02-27

  The present disclosure relates to bifunctional compounds, which find utility as modulators of alpha-synuclein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/ inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure. Such diseases or disorders are alpha-synucleinopathies or neurodegenerative diseases associated with alpha-synuclein accumulation and aggregation, such as e.g. Parkinson Disease, Alzheimer's Disease, dementia, dementia with Lewy bodies or multiple system atrophy, in particular Parkinson's Disease.

  本公开涉及双功能化合物，其作为α-突触核蛋白（目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端为Von Hippel-Lindau、cereblon、凋亡抑制蛋白或鼠双分子同源物2配体的双功能化合物，该配体与相应的E3泛素连接酶结合，另一端为与目标蛋白结合的基团，使得目标蛋白靠近泛素连接酶以促使目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性范围。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。这些疾病或紊乱是与α-突触核蛋白积累和聚集相关的α-突触核蛋白病或神经退行性疾病，例如帕金森病、阿尔茨海默病、痴呆症、带有Lewy小体的痴呆症或多系统萎缩，特别是帕金森病。
• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
  申请人：Arvinas, Inc.

  公开号：US20180179183A1

  公开（公告）日：2018-06-28

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为快速加速纤维肉瘤（RAF，如c-RAF、A-RAF和/或B-RAF；目标蛋白）的调节剂而发挥作用。具体而言，本公开涉及含有一端为Von Hippel-Lindau、cereblon、凋亡抑制蛋白或鼠双分子同源物2配体的双功能化合物，该配体与相应的E3泛素连接酶结合，并且另一端含有结合目标蛋白RAF的基团，使得目标蛋白与泛素连接酶靠近，以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性范围。本公开的化合物和组合物用于治疗或预防由目标蛋白的聚集或积累，或目标蛋白的构成性激活导致的疾病或紊乱。
• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ENHANCER OF ZESTE HOMOLOG 2 POLYPEPTIDE
  申请人：Arvinas, Inc.

  公开号：US20180177750A1

  公开（公告）日：2018-06-28

  The present disclosure relates to bifunctional compounds, which find utility as modulators of enhancer of zeste homolog 2 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为增强子锁定同源2的调节剂而发挥作用。具体而言，本公开涉及包含一端为Von Hippel-Lindau、cereblon、凋亡抑制蛋白或鼠双分子同源2配体的双功能化合物，该配体与相应的E3泛素连接酶结合，另一端含有结合目标蛋白的基团，使目标蛋白靠近泛素连接酶以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性范围。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。
• DIAZO BICYCLIC SMAC MIMETICS AND THE USES THEREOF
  申请人：Wang Shaomeng

  公开号：US20100273812A1

  公开（公告）日：2010-10-28

  The invention relates to diazo bicyclic mimetics of Smac which function as inhibitors of Inhibitor of Apoptosis Proteins. The invention also relates to the use of these mimetics for inducing apoptotic cell death and for sensitizing cells to inducers of apoptosis.

  该发明涉及一种Smac的重氮双环模拟物，其作为细胞凋亡抑制蛋白抑制剂。该发明还涉及利用这些模拟物诱导细胞凋亡死亡以及使细胞对凋亡诱导剂敏感的用途。