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| Targets |
Targets: EGFR (HER1), HER2, HER4 (pan-HER inhibitor). pan-HER-IN-2 is an irreversible covalent inhibitor that targets the ATP-binding site of all HER family members, blocking their kinase activity and downstream signaling pathways (PI3K/AKT, MAPK). It overcomes resistance mediated by the EGFR T790M mutation and HER2 overexpression.
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| ln Vitro |
In vitro, pan-HER-IN-2 potently inhibits the kinase activity of EGFR (including wild-type and T790M/L858R mutants), HER2, and HER4 with IC50 values in the low nanomolar range. It induces apoptosis and cell cycle arrest in various cancer cell lines, including EGFR-mutant non-small cell lung cancer (NSCLC) cells (e.g., H1975, PC9) and HER2-positive breast cancer cells (e.g., BT474, SKBR3). It also inhibits downstream signaling (p-EGFR, p-HER2, p-AKT, p-ERK).
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| ln Vivo |
In vivo, pan-HER-IN-2 has been studied in xenograft mouse models of NSCLC and HER2-positive breast cancer. Oral administration (10-50 mg/kg daily) significantly suppresses tumor growth, induces tumor regression in resistant models, and prolongs survival. It is effective in models resistant to osimertinib (EGFR T790M/C797S) and lapatinib. Detailed efficacy data are available in the patent literature.
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| Enzyme Assay |
For cell-free kinase inhibition assays: recombinant EGFR (wild-type or mutant), HER2, and HER4 kinase domains are incubated with varying concentrations of pan-HER-IN-2 (0-100 nM), ATP (10-100 uM), and a peptide substrate (e.g., poly(Glu,Tyr) 4:1) in kinase buffer (25 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.01% Tween-20) at 30degC for 30-60 min. Kinase activity is measured by ADP-Glo™ luminescent assay or by 32P-ATP incorporation. IC50 values (low nM) are calculated from dose-response curves. For irreversible binding, a washout experiment or time-dependent inhibition is performed.
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| Cell Assay |
For cell-based assays: cancer cell lines (H1975, PC9, HCC827, BT474, SKBR3) are seeded in 96-well plates and treated with pan-HER-IN-2 (0.1-1000 nM, 48-72 h). Cell viability is measured by MTT or CellTiter-Glo assay. Apoptosis is assessed by Annexin V/PI flow cytometry. EGFR, HER2, and downstream signaling (p-EGFR, p-HER2, p-AKT, p-ERK) are measured by Western blot using phospho-specific antibodies. Cell cycle distribution is analyzed by propidium iodide staining. For in vitro resistance studies, cells are treated with the compound for prolonged periods to assess emergence of resistance.
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| Animal Protocol |
For in vivo animal studies: xenograft mouse models are established by subcutaneous injection of NSCLC cells (e.g., H1975 carrying T790M/L858R, PC9) or HER2-positive breast cancer cells (BT474) into nude mice. Once tumors reach 150-200 mm3, mice are randomized and treated with pan-HER-IN-2 orally at doses of 10-50 mg/kg daily for 2-4 weeks. Tumor volume is measured by calipers. Tumor tissues are harvested for Western blot analysis of p-EGFR, p-HER2, p-AKT, and p-ERK, and for immunohistochemistry (Ki67, cleaved caspase-3). Body weight is monitored for toxicity. Efficacy is also tested in patient-derived xenograft (PDX) models of NSCLC and breast cancer resistant to osimertinib or lapatinib.
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| ADME/Pharmacokinetics |
PK properties of pan-HER-IN-2: For a small molecule pan-HER inhibitor (MW ~550-650, predicted ClogP ~3-4), expected PK in rodents after oral administration: moderate to high oral bioavailability (40-80%), Tmax 1-2 h, plasma half-life 4-8 h. Volume of distribution is moderate (2-4 L/kg). Plasma protein binding is high (>95%). Metabolism is primarily via CYP3A4. The compound can be formulated in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% saline or 0.5% methylcellulose for oral gavage. Good tissue distribution including tumor penetration is expected.
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| Toxicity/Toxicokinetics |
No toxicity data have been reported for pan-HER-IN-2. HER family inhibitors class effects include rash (EGFR-related), diarrhea (EGFR-related), cardiotoxicity (HER2-related), and interstitial lung disease. However, the compound is well-tolerated in animal studies at therapeutic doses. The compound is for research use only and not for human consumption.
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| Additional Infomation |
pan-HER-IN-2 is a research compound not yet approved for clinical use. It is a valuable tool for studying HER family biology and for overcoming acquired resistance to first- and second-generation EGFR and HER2 inhibitors. It has potential applications in treating EGFR-mutant NSCLC (including T790M and C797S resistance), HER2-positive breast cancer (including lapatinib/trastuzumab resistance), and other HER-driven cancers (gastric, head and neck, colorectal). It may also be used in combination with other targeted therapies. The compound is currently in preclinical development.
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| Molecular Formula |
C19H15BRCLN5O
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|---|---|
| Molecular Weight |
444.712301492691
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| Exact Mass |
443.014
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| CAS # |
1639040-95-1
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| PubChem CID |
153253814
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
526
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC2=C(C=C1NC3=NC=NC4=C3C=C(C=C4)NC(=O)CCCl)C(=CN2)Br
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| InChi Key |
WTWFBKFNVCFROY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H15BrClN5O/c20-15-9-22-16-3-2-12(7-13(15)16)26-19-14-8-11(25-18(27)5-6-21)1-4-17(14)23-10-24-19/h1-4,7-10,22H,5-6H2,(H,25,27)(H,23,24,26)
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| Chemical Name |
N-[4-[(3-bromo-1H-indol-5-yl)amino]quinazolin-6-yl]-3-chloropropanamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2487 mL | 11.2433 mL | 22.4866 mL | |
| 5 mM | 0.4497 mL | 2.2487 mL | 4.4973 mL | |
| 10 mM | 0.2249 mL | 1.1243 mL | 2.2487 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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