RET^WT (IC50 = 1.29 nM); RET^V804M (IC50 = 1.97 nM ); RET^V804M (IC50 = 0.99 nM)

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。相对于 EGFR，ONT-380 (ARRY-380) 选择性抑制受体酪氨酸激酶 HER2。在 HER2 过表达细胞系中，ONT-380 阻断 HER2 及其下游效应子 Akt 的增殖和磷酸化。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 ONT-380 可能具有阻断 HER2 信号传导的潜力，而不引起 EGFR 抑制的毒性。

在 ARRY-380 治疗组中，75% 的动物在第 43 天仍存活。ARRY-380 及其活性代谢物导致大脑 pErbB2 显着减少 (80%)。 ARRY-380 表现出显着的剂量相关肿瘤生长抑制作用（TGI；50 mg/kg/d 时抑制 50%，100 mg/kg/d 时抑制 96%），并在较高剂量下出现许多部分消退（与基线大小相比减少 > 50%） 9/12 动物的剂量水平。 ARRY-380（50 mg/kg/d）与曲妥珠单抗联合显示 98% 的 TGI，其中 9/12 只动物完全消退，两次部分消退。 ARRY-380 与曲妥珠单抗组合的剂量为 100 mg/kg/d 时，TGI 为 100%，并且所有动物均具有完全缓解。

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。

Experimental Design: [1]
ONT-380 was administered twice daily (BID) in continuous 28-day cycles. After a modified 3+3 dose-escalation design determined the MTD, the expansion cohort was enrolled. PK properties of ONT-380 and a metabolite were determined. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST).

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Results: [1]
Fifty patients received ONT-380 (escalation = 33; expansion = 17); 43 patients had HER2+ MBC. Median prior anticancer regimens = 5. Dose-limiting toxicities of increased transaminases occurred at 800 mg BID, thus 600 mg BID was the MTD. Common AEs were usually Grade 1/2 in severity and included nausea (56%), diarrhea (52%), fatigue (50%), vomiting (40%) constipation, pain in extremity and cough (20% each). 5 patients (19%) treated at MTD had grade 3 AEs (increased transaminases, rash, night sweats, anemia, and hypokalemia). The half-life of ONT-380 was 5.38 hours and increases in exposure were approximately dose proportional. In evaluable HER2+ MBC (n = 22) treated at doses ≥ MTD, the response rate was 14% [all partial response (PR)] and the clinical benefit rate (PR + stable disease ≥ 24 weeks) was 27%.

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200 mg/kg/d; oral

Mice with SKOV-3 tumor

Absorption, Distribution and Excretion
The Tmax for tucatinib ranges from 1 to 4 hours. One pharmacokinetic study revealed a Cmax of 1120 ng/mL after a dose of 350 mg twice daily with a Tmax ranging from 1 to 3 hours. The AUCtau was reported to be about 7120 hours×ng/mL.
In a study of radiolabled tucatinib, about 86% of the total dose was excreted in the feces and 4.1% was found in the urine. About 16% of the tucatinib dose recovered in the feces was identified as unchanged tucatinib.
The volume of distribution of tucatinib is about 1670 L. This drug penetrates the blood-brain barrier.
The apparent clearance is 148 L/h.

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Metabolism / Metabolites
Tucatinib is metabolized by CYP2C8 with some contributions from CYP3A.

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Biological Half-Life
A pharmacokinetic study revealed a half-life of approximately 5.38 hours. Prescribing information mentions a geometric mean half-life of about 8.21 hours.

Hepatotoxicity
In the prelicensure clinical trials of tucatinib in combination with trastuzumab and capecitabine in patients with metastatic and unresectable HER2 positive breast cancer, liver test abnormalities were frequent although usually self-limited and mild. Some degree of ALT elevations arose in 46% of those receiving tucatinib vs 27% treated with trastuzumab and capecitabine alone. Peak ALT levels rose to above 5 times the upper limit of normal (ULN) in 8% of the tucatinib treated subjects but in less than 1% of controls receiving trastuzumab and capecitabine alone. In a controlled trial enrolling 612 patients with breast cancer, 9 tucatinib treated patients developed ALT elevations and hyperbilirubinemia. Upon further evaluation, however, none of these cases of suspected significant liver injury were considered due to tucatinib, all patients having other possible reasons for liver injury and jaundice. There were no cases of tucatinib-associated liver failure or hepatotoxicity leading to death in any of the prelicensure studies. The product label for tucatinib recommends monitoring for routine liver tests before and every 3 weeks during therapy, and as clinically indicated.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of tucatinib during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during tucatinib therapy and for 1 week after the last dose. However, tucatinib is used in combination with trastuzumab and capecitabine. It is recommended that breastfeeding be suspended for 7 months after the use of trastuzumab.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Tucatinib is about 97% bound to plasma proteins.

[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.

Tucatinib is a kinase inhibitor drug used with [trastuzumab] and [capecitabine] in the treatment of unresectable or metastatic HER-2 positive breast cancer. It was developed by Seattle Genetics and approved by the FDA on April 17, 2020. Tucatinib is a promising new treatment for patients with metastatic breast cancer who have not responded adequately to other chemotherapy regimens.
Tucatinib is a Kinase Inhibitor. The mechanism of action of tucatinib is as a Tyrosine Kinase Inhibitor, and Cytochrome P450 3A Inhibitor, and P-Glycoprotein Inhibitor, and Cytochrome P450 2C8 Inhibitor.
Tucatinib is tyrosine kinase inhibitor that targets the human epidermal growth factor receptor 2 (HER2) and is used in combination with other antineoplastic agents in the treatment of refractory, advanced or metastatic HER2 positive breast and colorectal cancer. Serum aminotransferase elevations are common during therapy with tucatinib, but it has not been linked to episodes of clinically apparent liver injury with jaundice.
Tucatinib is an orally bioavailable inhibitor of the human epidermal growth factor receptor tyrosine kinase ErbB-2 (also called HER2) with potential antineoplastic activity. Tucatinib selectively binds to and inhibits the phosphorylation of ErbB-2, which may prevent the activation of ErbB-2 signal transduction pathways, resulting in growth inhibition and death of ErbB-2-expressing tumor cells. ErbB-2 is overexpressed in a variety of cancers and plays an important role in cellular proliferation and differentiation.

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Drug Indication
Tucatinib is indicated with [trastuzumab] and [capecitabine] for the treatment of adults diagnosed with advanced unresectable or metastatic HER2-positive breast cancer. This includes patients with brain metastases and those who have received one or more prior anti-HER2-based regimens in the metastatic setting. It is also indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval; thus, it is contingent upon verification and description of clinical benefit in confirmatory trials.
Tukysa is indicated in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2‑positive locally advanced or metastatic breast cancer who have received at least 2 prior anti‑HER2 treatment regimens.
Treatment of solid tumours
Treatment of breast malignant neoplasms

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Mechanism of Action
Mutations in the HER-2 gene are observed in some types of breast carcinoma. Tucatinib inhibits the tyrosine kinase enzyme of the HER-2 gene. Mutations of tyrosine kinase in the HER-2 gene lead to cascade effects of increased cell signaling and proliferation, resulting in malignancy. Results of in vitro studies show that tucatinib inhibits the phosphorylation of both HER-2 and HER-3, leading to downstream changes in MAPK and AKT signaling and cell proliferation. Anti-tumor activity occured in the cells that expressed HER-2. In vivo, tucatinib has been shown to inhibit HER-2 expressing tumors, likely by the same mechanism.

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Pharmacodynamics
By inhibiting tyrosine kinase, tucatinib exerts anti-tumor activity, reducing the size of HER-2 positive breast cancer tumors. In clinical trials, the regimen of tucatinib and [trastuzumab] showed enhanced activity both in vitro and in vivo when compared to either drug administered by itself.

C26H24N8O2

480.2022

480.202

C, 64.99; H, 5.03; N, 23.32; O, 6.66

937263-43-9

Tucatinib hemiethanolate;1429755-56-5

51039094

White to yellow solid powder

1.4±0.1 g/cm3

1.729

3.62

110.85

2

8

6

36

796

0

N1C2C(=CC(NC3OCC(C)(C)N=3)=CC=2)C(NC2C=C(C)C(OC3=CC4N(N=CN=4)C=C3)=CC=2)=NC=1

SDEAXTCZPQIFQM-UHFFFAOYSA-N

InChI=1S/C26H24N8O2/c1-16-10-17(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/h4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31)

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

ONT 380; ARRY380; ONT380; ARRY 380; ONT-380; Irbinitinib; ARRY-380; Tukysa; Tucatinib

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: ~96 mg/mL ( ~199.8 mM）
Water: <15 mg/mL
Ethanol: Insoluble

配方 1 中的溶解度: ≥ 2.62 mg/mL (5.45 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*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: ≥ 2.62 mg/mL (5.45 mM) (饱和度未知) in 5% DMSO + 95% (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。
*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 (4.33 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), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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 4 中的溶解度: 2.08 mg/mL (4.33 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), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将100μL 20.8mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，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 5 中的溶解度: ≥ 2.08 mg/mL (4.33 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900 μL 玉米油中，混合均匀。

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配方 6 中的溶解度: 5%DMSO+40%PEG300+5%Tween 80+50%ddH2O：0.8mg/ml

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配方 7 中的溶解度: 10 mg/mL (20.81 mM) in 30 % SBE-β-CD (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。

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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。