sabutoclax | 1228108-65-3

• 物质功能分类: 生物化工 - 抑制剂 - 细胞凋亡(Apoptosis)
• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: sabutoclax
• 英文别名: BI-97C1；2,3,5-trihydroxy-7-methyl-N-[(2R)-2-phenylpropyl]-6-[1,6,7-trihydroxy-3-methyl-5-[[(2R)-2-phenylpropyl]carbamoyl]naphthalen-2-yl]naphthalene-1-carboxamide
• CAS: 1228108-65-3
• 化学式: C₄₂H₄₀N₂O₈
• 分子量: 700.788
• InChiKey: RAYNZUHYMMLQQA-ZEQRLZLVSA-N

物化性质

• 熔点：
  >130°C (dec.)
• 沸点：
  905.9±65.0 °C(Predicted)
• 密度：
  1.358±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO（微溶）、乙酸乙酯（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  8.9
• 重原子数：
  52
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  180
• 氢给体数：
  8
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

Sabutoclax（BI-97C1）是一种pan-BcL-2抑制剂，作用于Bcl-xL、BcL-2、Mcl-1和Bfl-1的IC50分别为0.31 μM、0.32 μM、0.20 μM和0.62 μM。

体外研究

BI-97C1有效抑制人类前列腺癌、肺癌和淋巴瘤细胞系生长，EC50值分别为0.13 μM、0.56 μM 和 0.049 μM。对bax-/- bak-/- 细胞几乎没有细胞毒性。使用mda-7/IL-24与BI-97C1联合治疗方案可以诱导自噬，这有利于细胞凋亡，并相应地上调NOXA、使Bim累积以及激活Bax和Bak。

体内研究

BI-97C1能够有效作用于脾B细胞过度表达BcL-2的转基因小鼠，并对前列腺癌小鼠移植瘤模型具有强效抗肿瘤效果。Ad.5/3-mda-7 和 BI-97C1处理裸鼠和Hi-myc转基因小鼠，显著抑制人类PC移植瘤和自发诱导的PC生长。这些处理能抑制PC移植瘤和Hi-myc小鼠前列腺的肿瘤生长，并与TUNEL染色增加和Ki-67表达降低相关。

目标

Target	Value
Mcl-1 (Cell-free assay)	0.20 μM
Bcl-xL (Cell-free assay)	0.31 μM
BcL-2 (Cell-free assay)	0.32 μM
Bfl-1 (Cell-free assay)	0.62 μM

反应信息

• 作为产物：
  描述：

  (R,R)-1,1', 6,6',7,7'-hexamethoxy-3,3'-dimethyl-N5,N5'-bis(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide 在 三溴化硼 、 盐酸 、 水 作用下， 以 二氯甲烷 为溶剂， 反应 3.5h， 以25 mg的产率得到sabutoclax
  参考文献：
  名称：

  BI-97C1, an Optically Pure Apogossypol Derivative as Pan-Active Inhibitor of Antiapoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins

  摘要：

  In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here the synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97Cl), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-l, and Bfl-l with IC(50) values of 0.31, 0.32, 0.20, and 0.62 mu M, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer, and lymphoma cell lines with EC(50) values of 0.13, 0.56, and 0.049 mu M, respectively, and shows little cytotoxicity against bax(-/-)bak(-/-) cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer.

  DOI：

  10.1021/jm1001265

文献信息

• COMBINATIONS COMPRISING AN INHIBITOR OF AN ANTI-APOPTOTIC PROTEIN, SUCH AS BCL-2, BCL-XL, BCLW OR MCL-1, AND A NOTCH SIGNALING PATHWAY INHIBITOR FOR TREATING CANCER
  申请人：Cellestia Biotech AG

  公开号：EP4008324A1

  公开（公告）日：2022-06-08

  The present invention relates to pharmaceutical combinations comprising an inhibitor of an anti-apoptotic protein and a NOTCH signaling pathway inhibitor and their use in a method for the prevention, delay of progression or treatment of cancer in a subject.

  本发明涉及由抗凋亡蛋白抑制剂和 NOTCH 信号通路抑制剂组成的药物组合及其在预防、延缓或治疗受试者癌症的方法中的用途。
• Chemical entities that kill senescent cells for use in treating age-related disease
  申请人：Unity Biotechnology, Inc.

  公开号：US10195213B2

  公开（公告）日：2019-02-05

  Disclosed herein are compounds that are effective for treatment of various disease states associated with senescence. The disclosed compounds can be used to eliminate senescent cells for disease treatment. The dosing of the compounds includes both single administration and regimens of cycling dosages.

  本文公开的化合物可有效治疗与衰老有关的各种疾病状态。所公开的化合物可用于消除衰老细胞以治疗疾病。化合物的给药方式包括单次给药和循环给药。
• Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
  申请人：ZHEJIANG DTRM BIOPHARMA CO. LTD.

  公开号：US10596183B2

  公开（公告）日：2020-03-24

  Described herein are combination therapies for cancer (such as lymphoid malignancies) and immune diseases (such as autoimmune diseases and inflammatory diseases). The therapies comprise the combined use of inhibitors of BTK, mTOR kinase, and Bcl-2 or their signaling pathways, and immunomodulatory drugs. Also described are pharmaceutical compositions and kits comprising these inhibitors.

  本文描述的是癌症（如淋巴恶性肿瘤）和免疫性疾病（如自身免疫性疾病和炎症性疾病）的联合疗法。这些疗法包括联合使用 BTK、mTOR 激酶和 Bcl-2 或其信号通路的抑制剂以及免疫调节药物。还描述了包含这些抑制剂的药物组合物和试剂盒。
• MECHANISM OF RESISTANCE TO BET BROMODOMAIN INHIBITORS
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：EP3334725A1

  公开（公告）日：2018-06-20
• PHARMACEUTICAL COMPOSITIONS AND THEIR USE FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASES
  申请人：He Wei

  公开号：US20160324878A1

  公开（公告）日：2016-11-10

  Described herein are combination therapies for cancer (such as lymphoid malignancies) and immune diseases (such as autoimmune diseases and inflammatory diseases). The therapies comprise the combined use of inhibitors of BTK, mTOR kinase, and Bcl-2 or their signaling pathways, and immunomodulatory drugs. Also described are pharmaceutical compositions and kits comprising these inhibitors.