HER2 (IC50 = 8 nM)[1]

在基于细胞的实验中，图卡替尼半乙醇盐对 HER2 的选择性比 EGFR 高大约 500 倍，并且它对纯化的 HER2 酶表现出纳摩尔级活性。与 EGFR 相比，tucatinib 优先抑制受体酪氨酸激酶 HER2[1]。在 HER2 过表达细胞系中，tutatinib 抑制 HER2 及其下游效应子 Akt 的生长和磷酸化。图卡替尼可能能够通过微弱抑制磷酸化和增殖来阻止 EGFR 过表达细胞系中的 HER2 信号转导，而不会产生 EGFR 抑制的负面副作用[1]。

当每种药物以最大耐受剂量给药时，图尼替尼半乙醇盐（ONT-380 半乙醇盐，200 mg/kg/d）表现出生存获益[1]。 tucacitabine 及其活性代谢物显着减少脑 pErbB2 的量 (80%)[2]。图卡替尼 (ARRY-380) 半乙醇盐表现出显着的肿瘤生长抑制作用（TGI；50 mg/kg/d 时抑制 50%，100 mg/kg/d 时抑制 96%），并有多个部分消退（减少 > 50%）从基线大小）在较高剂量水平下在 9/12 动物中观察到。当与曲妥珠单抗联合使用时，tutatinib (50 mg/kg/d) 表现出 98% 的 TGI，12 只动物中有 9 只出现了两次部分消退和完全消退[3]。

Irbinitinib，以前称为 ARRY-380 和 ONT-380 或 Tucatinib，是一种有效的选择性 HER2 小分子抑制剂，IC50 值为 8 nM，对截短的 p95-HER2 具有同等效力，并且对 HER2 的选择性高出 500 倍。 HER2 与 EGFR。厄比尼替尼通过阻断 HER2 及其下游效应器 Akt 的增殖和磷酸化发挥作用。相比之下，在 EGFR 过表达细胞系中，它对磷酸化和增殖的抑制较弱，这表明厄比尼替尼可能具有阻断 HER2 信号传导的潜力，而不引起 EGFR 抑制的毒性。因此，它具有用作抗癌剂的潜力。

ONT-380 对纯化的 HER2 酶具有纳摩尔级活性，并且在基于细胞的测定中，对 HER2 的选择性大约是 EGFR 的 500 倍。在 EGFR 过表达细胞系中，它对磷酸化和增殖有微弱的抑制作用，这表明 Irbinitinib 可能具有阻断 HER2 信号传导的潜力，而不引起 EGFR 抑制的毒性。

Animal/Disease Models: Female nude mice[3].
Doses: 200 mg/kg/d.
Route of Administration: PO, daily.
Experimental Results: demonstrated anti-tumor activity and benefited survival.

[1]. Phase 1 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 Jan 4. pii: clincanres.1496.2016.

[2]. Abstract: In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 852. doi:1538-7445.AM2012-852.

[3]. In Vivo Activity of ARRY-380, a Potent, Small Molecule Inhibitor of ErbB2 in Combination with RP-56976. Cancer Research.

ARRY-380 is an orally active, potent small molecule tyrosine kinase inhibitor targeting ErbB2. The compound is a reversible, ATP-competitive inhibitor with nanomolar potency against ErbB2 in both in vitro and in cell-based assays. This compound has very good in vivo and in vitro PK/ADME properties and has shown excellent activity in numerous mouse tumor models including breast (BT-474, MDA-MB-453), ovarian (SKOV-3) and gastric (N87) carcinoma models. Here we demonstrate excellent single agent activity and combinability with trastuzumab, docetaxel or bevacizumab in breast and ovarian carcinoma models. For the BT-474 studies, female SCID beige mice were implanted with tumor fragments. For the SKOV-3 tumor studies, female nude mice were inoculated with cells subcutaneously in the flank. Animals received: doses of ARRY-380 ranging up to 200 mg/kg/d, PO; and/or trastuzumab at 20 mg/kg, IP, Q3D or QW; and/or docetaxel at 10 mg/kg, IV, Q3D; and/or bevacizumab at 10 mg/kg, IP, Q4D x3. Tumor size was measured at regular intervals and subsets of animals were monitored for up to 90 days to determine tumor-free survival. In the BT-474 model, ARRY-380 demonstrated significant dose-related tumor growth inhibition (TGI; 50% at 50 mg/kg/d and 96% at 100 mg/kg/d) with numerous partial regressions (>50% reduction from baseline size) at the higher dose level in 9/12 animals. One complete response was observed at the higher dose. Trastuzumab alone provided a 45% TGI with no regressions. ARRY-380 (50 mg/kg/d) in combination with trastuzumab showed a 98% TGI with complete regressions in 9/12 animals and two partial regressions. At dose of 100 mg/kg/d of ARRY-380 in combination with trastuzumab, there was 100% TGI and all animals had complete responses. Docetaxel as a single agent produced a 55% TGI with no regressions. In combination with ARRY-380 (50 mg/kg/d), there was an 81% TGI and five partial regressions. In the SKOV-3 model, ARRY-380 demonstrated significant dose-related tumor growth inhibition (TGI; 39% at 50 mg/kg, BID and 96% at 100 mg/kg, BID) with partial regressions (>50% reduction from baseline size) at the higher dose level in all animals. Bevacizumab alone provided a 55% TGI with no regressions. ARRY-380 (50 mg/kg, BID) in combination with bevacizumab showed 80% TGI with partial responses in 7/8 animals and one stable disease. From this work we have demonstrated superb single agent activity for ARRY-380 in the BT-474 human breast carcinoma xenograft model and the SKOV-3 human ovarian carcinoma model. In addition, ARRY-380 has shown additive activity and tolerability with trastuzumab, docetaxel and bevacizumab. ARRY-380 has entered Phase I clinical trials in patients with advanced cancers.[3]

C26H24N8O2.1/2C2H6O

503.57

1006.446

1429755-56-5

Tucatinib;937263-43-9

162623678

White to off-white solid powder

242Ų

5

17

12

75

799

0

UGAFQGGOUGJBMF-UHFFFAOYSA-N

InChI=1S/2C26H24N8O2.C2H6O/c2*1-16-10-17(5-7-22(16)36-19-8-9-34-23(12-19)28-15-30-34)31-24-20-11-18(4-6-21(20)27-14-29-24)32-25-33-26(2,3)13-35-25;1-2-3/h2*4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31);3H,2H2,1H3

6-N-(4,4-dimethyl-5H-1,3-oxazol-2-yl)-4-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine hemiethanolate

Irbinitinib hemiethanolate; ONT380; ARRY-380 hemiethanolate; ARRY380; ONT-380 hemiethanolate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 125 mg/mL (248.23 mM)
H2O: < 0.1 mg/mL

配方 1 中的溶解度: 2.08 mg/mL (4.13 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.08 mg/mL (4.13 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (4.13 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。