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ARRY-380

现货
Catalog No.
A8366
酪氨酸激酶HER2和P95-HER2抑制剂。
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 2,710.00
现货
5mg
¥ 1,320.00
现货
10mg
¥ 2,460.00
现货
50mg
¥ 7,920.00
现货

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Background

IC50: 8 nM (HER2)

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. ARRY-380 is an orally bioavailable inhibitor of the human epidermal growth factor receptor tyrosine kinase ErbB-2 (also called HER2) with potential antineoplastic activity.

In vitro: ARRY-380 is reported to be a reversible, ATP-competitive inhibitor with nanomolar activity against HER2 enzyme. In cell-based assays, ARRY-380 is ~500-fold selective for HER2 vs. EGFR and is equipotent against truncated p95-HER2 [1].

In vivo: ARRY-380 treatment significantly enhances survival in two ErbB2 driven intracranial tumor xenograft models, with superior activity compared to other ErbB2 agents in these studies. Additionally, ARRY-380 has demonstrated durable clinical activity in heavily pre-treated patients with ErbB2+ MBC. These preclinical and clinical data suggest that ARRY-380 may provide benefit to patients with ErbB2+ MBC with brain metastases. These preclinical and clinical data suggest that ARRY-380 may provide benefit to patients with ErbB2+ MBC with brain metastases and warrants further study [2].

Clinical trial: In a phase 1 clinical trial, 15 patients have been treated in 5 dosing cohorts at doses of 25 to 300 mg BID. No DLTs have been observed and drug-related adverse events have included Grade 1 nausea, rash and fatigue and Grade 2 fatigue in 2 patients at the 200 mg BID dose level. Preliminary PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours and a mean t1/2 of 4.6 hours across all cohorts. Two patients with HER2+ breast cancer have had stable disease for ≥ 4 months with no significant toxicity. One of these two patients had a notable reduction in liver metastases (28%) after 2 cycles of ARRY-380 and is currently on study.These findings indicate ARRY-380 has demonstrated an acceptable safety and PK profile and preliminary signs of clinical benefit. Dose escalation continues to determine the MTD [3].

References:
[1] S.  L. Moulder, V. Borges, S. K. L. Chia, T. Baetz, E. Barrett, J. Garrus, K. Guthrie, C. Kass, E. Laird, J. Lyssikatos, F. Marmsater, E. Wallace. ARRY-380, a Selective HER2 Inhibitor: From Drug Design to Clinical Evaluation. Poster of AACR-NCI-EORTC, Nov 12-16, 2011, San Francisco, CA.
[2] Victoria Dinkel, Deborah Anderson, Shannon Winski, Jim Winkler, Kevin Koch and Patrice Lee.  ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice. Poster available at www.arraybiopharma.com
[3] S.  Chia, T. Baetz, S. D'Aloisio, G. Fernetich, B. Freeman, E. Barrett, C. Kass, J. Kang, B. Sajan, S. Moulder, and J. Garrus. A Phase 1 Study To Assess the Safety, Tolerability and Pharmacokinetics of ARRY-380 – An Oral Inhibitor of HER2. Cancer Res 2009;69(24 Suppl):Abstract nr 5111.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt569.63
Cas No.937265-83-3
FormulaC29H27N7O4S
SynonymsARRY380; ARRY 380
Solubility≥28.5mg/mL in DMSO
Chemical Name6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazolin-4-amine
SDFDownload SDF
Canonical SMILESCC1=C(C=CC(=C1)NC2=NC=NC3=C2C=C(C=C3)C4=CC=C(O4)CNCCS(=O)(=O)C)OC5=CC6=NC=NN6C=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

BT474细胞,NIH-3T3细胞

溶解方法

在DMSO中的溶解度>28.5mg/mL。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月

反应时间

N/A

应用

ARRY-380是ErbB2(Her2人类表皮生长因子受体2)的具有口服活性和选择性的小分子抑制剂。它抑制ErbB2的IC50为14nm,在BT474细胞中它可以抑制ErbB2的磷酸化,其IC50为21nm。ARRY-380也可以强有效的抑制AKT(蛋白激酶B)的磷酸化,诱导BT474细胞的凋亡和生长抑制。在稳定转染了有持续活性的ErbB2 (3T3-rErbB2)的NIH-3T3细胞中,ARRY-380可以显著抑制肿瘤生长。

临床实验[2]:

疾病模型

HER2阳性的癌症患者(包括HER2阳性的转移性乳腺癌患者)

剂量

剂量递增队列(HER2阳性的癌症):在循环1中从25 mg(每天2次)开始递增的,按照计划依次为50, 100, 200, 300, 500, 650 和800 mg剂量的药物,每日两次,连续28天。(最大耐受含量为600mg,每日两次)扩展队列(HER2阳性的转移性乳腺癌患者):在循环2中600mg,每日两次,连续28天

应用

ARRY-380与传统的现在在使用的HER2/EGFR(表皮生长因子受体)的双重抑制剂不同,它有着较低的腹泻和疹的发生率和严重程度,并且在严重的预先处理过的HER2阳性的转移性乳腺癌患者中有着较好的抗肿瘤活性,这对它的未来发展是有利的。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Pheneger, T., et al., In vitro and in vivo activity of ARRY-380: A potent, small molecule inhibitor of ErbB2. Presented at the American Association of Cancer Research 100th Annual Meeting Apr 18-22, 2009; Cancer Res 69 (abstr 1795).

[2]. Moulder SL1, Borges VF2, et al, Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC). Clin Cancer Res. 2017 Jul 15;23(14):3529-3536. doi: 10.1158/1078-0432.CCR-16-1496. Epub 2017 Jan 4.

生物活性

描述 ARRY-380是一种口服生物可利用的、有效的和选择性的小分子酪氨酸激酶HER2和P95-HER2抑制剂,IC50值分别为8 nM和7 nM。
靶点 p95-HER2 HER2 EGFR      
IC50 7 nM 8 nM 4 μM      

质量控制

化学结构

ARRY-380