- Epidermal growth factor receptor (EGFR) (Ki values in the low nanomolar range for various EGFR mutants)
- ERBB2 (also known as HER2)
- ERBB family members in general, as it is a pan - ERBB inhibitor [1]

- Potently inhibited the activity of EGFR - activating mutations as well as the EGFR T790M resistance mutation in vitro. In cell - based assays, it showed significant inhibitory effects on the phosphorylation of EGFR mutants, blocking the downstream signaling pathways related to cell proliferation, such as the MAPK and AKT pathways. For example, in lung cancer cell lines with EGFR - activating mutations or the T790M resistance mutation, Dacomitinib treatment led to a dose - dependent decrease in cell viability and proliferation [1]
- Inhibited the proliferation of HER2 - amplified breast cancer cell lines resistant to Anti - Human HER2 and GW572016. In breast cancer cell lines with HER2 amplification, Dacomitinib treatment inhibited cell growth in a dose - dependent manner. It also effectively reduced the phosphorylation of HER2 and its downstream signaling molecules, such as AKT and ERK, which are crucial for cell survival and proliferation [2]

- Demonstrated effectiveness in lung cancer models with EGFR and ERBB2 mutations that are resistant to ZD1839 (gefitinib). In xenograft mouse models of lung cancer with EGFR - activating mutations or ERBB2 mutations, oral administration of Dacomitinib caused significant tumor regression. Tumor growth was inhibited, and the overall survival of the mice was improved compared to the control group. The drug achieved this by inhibiting the activation of EGFR and ERBB2 in tumor tissues, reducing the production of pro - survival and pro - proliferative factors [1]

- For the lung cancer cell lines: Lung cancer cell lines with different EGFR mutations (such as activating mutations and the T790M resistance mutation) were cultured in appropriate growth media. Cells were seeded in 96 - well plates at a specific density. After an overnight incubation to allow cell attachment, Dacomitinib was added to the wells at various concentrations (ranging from low nanomolar to micromolar levels). Cell viability was then measured after a certain incubation period (usually 48 - 72 hours) using methods like the MTT assay or ATP - based cell viability assays. The inhibition of cell proliferation was calculated based on the absorbance or luminescence values obtained from these assays, and dose - response curves were generated to determine the IC50 values [1]
- For the breast cancer cell lines: HER2 - amplified breast cancer cell lines were cultured in suitable media. Cells were plated in 96 - well plates. After cell attachment, Dacomitinib was added at different concentrations. Cell growth was monitored over time, for example, by counting the number of cells at specific time points (such as 24, 48, and 72 hours) using a cell counter or by measuring the metabolic activity of the cells with assays like the XTT assay. Western blot analysis was also performed on cell lysates after Dacomitinib treatment. The cell lysates were prepared by lysing the cells in appropriate lysis buffers. Proteins were separated by SDS - PAGE electrophoresis and then transferred to nitrocellulose membranes. The membranes were probed with antibodies against HER2, phosphorylated HER2, AKT, phosphorylated AKT, ERK, and phosphorylated ERK to assess the impact of Dacomitinib on the HER2 signaling pathway [2]

- In the lung cancer xenograft models: Human lung cancer cell lines with EGFR or ERBB2 mutations were subcutaneously injected into the flanks of nude mice. Once the tumors reached a certain volume (usually around 100 - 200 mm³), the mice were randomly divided into treatment and control groups. Dacomitinib was formulated in a suitable vehicle (such as a mixture of DMSO and PEG 400 in saline). The drug was administered orally to the treatment group mice at a specific dose (e.g., 10 - 50 mg/kg) once daily for a defined period (usually 2 - 4 weeks). Tumor volumes were measured twice a week using calipers, and the body weights of the mice were also monitored. Tumor volume was calculated using the formula: volume = length × width² × 0.5. At the end of the treatment period, the mice were sacrificed, and tumors were excised for further analysis, such as immunohistochemistry to assess the expression of EGFR, ERBB2, and their phosphorylated forms [1]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the clinical use of dacomitinib during lactation. Because dacomitinib binds to plasma proteins at a rate of up to 98%, its concentration in breast milk is likely to be low. However, given its potential toxicity to breastfed infants and its 70-hour half-life, the manufacturer recommends discontinuing breastfeeding during dacomitinib treatment and for at least 17 days after the last dose.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

[1]. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to ZD1839. Cancer Res. 2007 Dec 15;67(24):11924-32.

[2]. Dacomitinib (PF-00299804), an irreversible Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to Anti-Human HER2 and GW572016. Mol Cancer Ther. 2012 Sep;11(9):1978-87.

[3]. Dacomitinib in the Management of Advanced Non-Small-Cell Lung Cancer. Drugs. 2019 Jun;79(8):823-831.

Dacomitinib is an irreversible pan-ERBB inhibitor. It covalently binds to nucleophilic cysteine residues at the ATP-binding site in the catalytic domain of ERBB family members, resulting in irreversible inhibition of their tyrosine kinase activity. This inhibition blocks downstream signaling cascades that are essential for cell proliferation, survival, and migration, thus dacomitinib is a potential therapeutic agent for cancers with ERBB family mutations and/or amplifications [1]. Dacomitinib is a highly selective, orally bioavailable small molecule inhibitor of HER family tyrosine kinases with potential antitumor activity. Dacomitinib specifically and irreversibly binds to and inhibits human Her-1, Her-2, and Her-4, thereby inhibiting the proliferation of tumor cells that overexpress these receptors and inducing their apoptosis.

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Drug Indications
Vizimpro is indicated as a monotherapy for first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations. The application of targeted therapy in the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a significant milestone in the treatment of advanced lung cancer. Several generations of EGFR tyrosine kinase inhibitors are currently available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor, and early clinical studies have shown its efficacy in NSCLC. In the recently published ARCHER 1050 phase III study, daily oral administration of 45 mg dacomitinib as first-line treatment was superior to the first-generation reversible EGFR tyrosine kinase inhibitor gefitinib in improving progression-free survival and overall survival. Currently, there is no prospective evidence to support the use of dacomitinib as a follow-up treatment in patients who have previously received chemotherapy or first-generation EGFR tyrosine kinase inhibitors (such as gefitinib and erlotinib). Dacomitinib has not shown any benefit in unselected NSCLC patients, and its use should be limited to patients with known EGFR-sensitive mutations. Compared with first-generation EGFR inhibitors, dacomitinib has more common toxic reactions (such as diarrhea, rash, stomatitis, and paronychia). Patients’ overall quality of life was maintained when evaluated in the phase III study. Overall, dacomitinib is an important first-line treatment for patients with EGFR-mutant non-small cell lung cancer, suitable for patients in good overall condition, and its toxic reactions can be well controlled. [3]

C24H27CLFN5O3

487.95428776741

487.178

C, 59.08; H, 5.58; Cl, 7.26; F, 3.89; N, 14.35; O, 9.84

1042385-75-0

Dacomitinib;1110813-31-4;Dacomitinib-d10 dihydrochloride;Dacomitinib-d10

70693519

White to light yellow solid powder

5.751

3

8

7

34

665

0

ClC1=C(C=CC(=C1)NC1=C2C(C=C(C(=C2)NC(/C=C/CN2CCCCC2)=O)OC)=NC=N1)F.O

BSPLGGCPNTZPIH-IPZCTEOASA-N

InChI=1S/C24H25ClFN5O2.H2O/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31;/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29);1H2/b6-5+;

(E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide;hydrate

Dacomitinib; Dacomitinib monohydrate; PF-00299804; PF00299804; PF 00299804; PF299804; PF-299804; PF 299804; PF-299; PF299; PF 299; PF-00299804-03; Vizimpro

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)