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BMS-833923

现货
Catalog No.
A3258
Smoothened抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 450.00
现货
10mg
¥ 700.00
现货
50mg
¥ 2,000.00
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Background

BMS-833923 is an orally bioavailable and selective antagonist of smoothened (SMO) with IC50 value of 5.8 nM in NIH3T3 cell line [1].
The Hedgehog (Hh) signaling is a critical pathway involved in embryonic development and in tissue maintenance and repair in adults. It consists of the Hh ligands, the transmembrane receptors Patched 1 and 2, the G-protein- coupled receptor-like protein SMO and the glioma-associated oncogene transcription factors GLI1 to 3. The aberrant activation of Hh pathway, both mutational and epigenetic, is found to be associated with multiple aspects of tumorigenesis in various tumor cells. As a smoothened inhibitor, BMS-833923 can block the binding of cyclopamine (a naturally occurring SMO inhibitor) to SMO. It showed potent Hh pathway inhibitory activity with IC50 values at nanomolar in multiple cell-based assays. BMS-833923 also potently inhibited Hh pathway in medulloblastoma and pancreatic carcinoma xenograft models [1, 2 and 3].
In vitro, BMS-833923 inhibited the expression of GLI1 and PTCH1 in cell lines expressing wild-type SMO or activated mutant SMO with IC50 values in the range from 6 to 35 nM. In the FACS-based binding assays, it does-dependently suppressed cyclopamine binding to SMO with IC50 value of 21 nM. In the esophageal adenocarcinoma cell lines OE19 and OE33, treatment of BMS-833923 significantly reduced cell proliferation with IC50 values of both 10 μM. Besides that, BMS-833923 was found to inhibit the growth of multiple myeloma cells and the proportion of ALDH+ cancer stem cells. It also inhibited the growth of many other tumor cells derived from patients with hematological malignancies including ALL, AML and CML [3 and 4].
In animal models with medulloblastoma and pancreatic carcinoma xenografts, administration of BMS-833923 at single oral dose showed robust inhibition of Hh pathway. In a rat model with gastroesophageal reflux disease, the administration of BMS-833923 at dose of 10 mg/kg/day resulted in the decreased development of both Barrett esophagus and esophageal adenocarcinoma by 35.7% [3 and 5].
References:
[1] Siu L L, Papadopoulos K P, Alberts S, et al. A first-in-human phase 1study of an oral hedgehog pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors. Mol Cancer Ther, 2009, 8(12 Suppl): A55.
[2] Justilien V, Fields A P. Molecular Pathways: Novel Approaches for Improved Therapeutic Targeting of Hedgehog Signaling in Cancer Stem Cells. Clinical Cancer Research, 2015, 21(3): 505-513.
[3] Gendreau S B, Hawkins D, Ho C P, et al. Abstract B192: Preclinical characterization of BMS‐833923 (XL139), a hedgehog (HH) pathway inhibitor in early clinical development. Molecular Cancer Therapeutics, 2009, 8(12 Supplement): B192-B192.
[4] Zaidi A H, Komatsu Y, Kelly L A, et al. Smoothened inhibition leads to decreased proliferation and induces apoptosis in esophageal adenocarcinoma cells. Cancer investigation, 2013, 31(7): 480-489.
[5] Gibson M K, Zaidi A H, Davison J M, et al. Prevention of Barrett esophagus and esophageal adenocarcinoma by smoothened inhibitor in a rat model of gastroesophageal reflux disease. Annals of surgery, 2013, 258(1): 82-88.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt473.57
Cas No.1059734-66-5
FormulaC30H27N5O
SynonymsBMS 833923;BMS833923;XL-139;XL139;XL 139
Solubility≥47.4 mg/mL in DMSO, ≥5.14 mg/mL in EtOH with ultrasonic and warming, <2.6 mg/mL in H2O
Chemical NameN-[2-methyl-5-(methylaminomethyl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide
SDFDownload SDF
Canonical SMILESCC1=C(C=C(C=C1)CNC)NC(=O)C2=CC=C(C=C2)NC3=NC4=CC=CC=C4C(=N3)C5=CC=CC=C5
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验[1]:

细胞系

OE19(JROECL19)和OE33(JROECL33)食管腺癌(EAC)细胞系

溶解方法

该化合物在DMSO中的溶解度大于47.4 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

0-100 μM,24和48小时

应用

在OE19和OE33细胞中,BMS-833923(10 μM)抑制细胞增殖,IC50为10 μM。BMS-833923(25 μM)完全抑制细胞增殖。在OE19和OE33细胞中,BMS-833923(10 μM)处理分别产生82和73.4%的凋亡细胞。

动物实验 [2,3]:

动物模型

成神经管细胞瘤和胰腺癌异种移植小鼠模型,具有胃食管反流病的雄性Sprague-Dawley大鼠

给药剂量

口服,10 mg/kg

应用

在成神经管细胞瘤和胰腺癌异种移植物动物模型中,单次口服给药BMS-833923抑制Hh通路。在具有胃食管反流病的大鼠模型中,10 mg/kg/day的剂量的BMS-833923导致巴雷特食管和食管腺癌的发展减少35.7%。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Zaidi A H, Komatsu Y, Kelly L A, et al. Smoothened inhibition leads to decreased proliferation and induces apoptosis in esophageal adenocarcinoma cells. Cancer investigation, 2013, 31(7): 480-489.

[2]. Gendreau S B, Hawkins D, Ho C P, et al. Abstract B192: Preclinical characterization of BMS‐833923 (XL139), a hedgehog (HH) pathway inhibitor in early clinical development. Molecular Cancer Therapeutics, 2009, 8(12 Supplement): B192-B192.

[3].Gibson M K, Zaidi A H, Davison J M, et al. Prevention of Barrett esophagus and esophageal adenocarcinoma by smoothened inhibitor in a rat model of gastroesophageal reflux disease. Annals of surgery, 2013, 258(1): 82-88.

生物活性

Description BMS-833923是一种口服生物可利用的Smoothened小分子抑制剂,IC50值为6-35 nM。
靶点 Smoothened          
IC50 6-35 nM          

质量控制

化学结构

BMS-833923