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| Targets |
HKI-357 targets the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (ERBB2, also known as HER2). It acts as an irreversible dual inhibitor, binding covalently to these receptor tyrosine kinases and preventing their activation. By inhibiting EGFR and ERBB2, it blocks downstream signaling pathways such as MAPK and AKT, which are critical for cell proliferation and survival.
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| ln Vitro |
In NCI-H1975 cells, ligand-induced EGFR autophosphorylation and its downstream signaling are efficiently inhibited by HKI-357 (0.01-10 μM) as shown by AKT and MAPK phosphorylation [1]. In parental NCI-H1650 cells bearing the delE746-A750 EGFR mutation, HKI-357 likewise potently suppresses EGFR autophosphorylation (measured at position Y1068) as well as AKT and MAPK phosphorylation [1].
In vitro, HKI-357 effectively suppresses ligand-induced EGFR autophosphorylation at the Y1068 site, as well as downstream AKT and MAPK phosphorylation in cancer cell lines such as NCI-H1975. The compound demonstrates potent inhibitory activity with IC50 values of 34 nM for EGFR and 33 nM for ERBB2. Its irreversible binding mechanism ensures sustained inhibition of these kinases. |
| ln Vivo |
In vivo efficacy studies for HKI-357 have been conducted in preclinical cancer models. As an irreversible dual EGFR/ERBB2 inhibitor, the compound has shown potential in reducing tumor growth in xenograft models. However, specific in vivo data regarding dosing, tumor growth inhibition rates, and survival benefits are not detailed in the available literature. Further studies are required to fully characterize its in vivo antitumor activity and therapeutic potential.
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| Enzyme Assay |
In vitro enzyme assays for HKI-357 typically involve kinase inhibition studies using recombinant EGFR and ERBB2 proteins. The kinases are incubated with increasing concentrations of the compound (0.01-10 μM) and ATP in kinase assay buffer. Phosphorylation of specific peptide substrates is measured using radioactive ³³P-ATP incorporation followed by filter binding and scintillation counting, or through luminescence-based assays such as ADP-Glo. IC50 values are calculated from dose-response curves by nonlinear regression.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: NCI-H1975 bronchoalveolar cell line Tested Concentrations: 0.01, 0.01, 0.1, 1 and 10 μM Incubation Duration: Experimental Results: Inhibition of ligand-induced EGFR autophosphorylation and its downstream signals AKT and MAPK phosphorylation change. For in vitro cell-based assays, cancer cell lines such as NCI-H1975 are cultured in appropriate media and treated with HKI-357 at concentrations ranging from 0.01-10 μM. EGFR inhibition is confirmed by measuring the phosphorylation of EGFR (Y1068), AKT, and MAPK via Western blot. Cell viability and proliferation are assessed by MTT or CellTiter-Glo assays. The compound's irreversible binding can be confirmed by washout experiments. |
| Animal Protocol |
In vivo animal studies with HKI-357 are conducted in mouse xenograft models of EGFR/ERBB2-driven cancers. Immunodeficient mice are subcutaneously implanted with human cancer cell lines. When tumors reach a certain size, mice are treated with HKI-357 orally or intraperitoneally at doses determined from pharmacokinetic studies. Tumor volume and body weight are monitored regularly. At study endpoint, tumors are excised for histopathological and molecular analyses.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of HKI-357 are characteristic of small molecule kinase inhibitors. The compound is soluble in DMSO and is typically administered orally or intraperitoneally in preclinical studies. Detailed pharmacokinetic parameters including oral bioavailability, Cmax, Tmax, AUC, and half-life are determined in preclinical species. The compound's irreversible binding mechanism may contribute to prolonged pharmacodynamic effects.
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| Toxicity/Toxicokinetics |
HKI-357 is a research compound and is not approved for human therapeutic use. In preclinical studies, it has shown a manageable safety profile at pharmacological doses. As an irreversible kinase inhibitor, it may have effects on normal tissues that express EGFR and ERBB2. Standard laboratory safety precautions should be followed when handling the compound. Comprehensive toxicology studies would be required for therapeutic development.
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| References | |
| Additional Infomation |
HKI 357 is being studied in clinical trial NCT00550381 (a study evaluating the safety, tolerability and pharmacokinetics (PK) of oral administration of HKI-357 in healthy subjects).
HKI-357 is a novel, potent, and irreversible dual inhibitor of EGFR and ERBB2 (HER2) with IC50 values of 34 nM and 33 nM, respectively. It suppresses EGFR autophosphorylation at Y1068 and inhibits downstream AKT and MAPK signaling. The compound has a molecular formula of C31H29ClFN5O3 and is available as a free base (CAS: 848133-17-5) or maleate salt (CAS: 915942-25-5). HKI-357 is intended for research purposes only and is not FDA-approved. |
| Molecular Formula |
C₃₁H₂₉CLFN₅O₃
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|---|---|
| Molecular Weight |
574.05
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| Exact Mass |
573.194
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| Elemental Analysis |
C, 64.86; H, 5.09; Cl, 6.18; F, 3.31; N, 12.20; O, 8.36
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| CAS # |
848133-17-5
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| Related CAS # |
848133-17-5;915942-25-5;
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| PubChem CID |
11238512
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| Appearance |
Off-white to yellow solid powder
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| LogP |
6.747
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
41
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| Complexity |
915
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N(C1C=CC(OCC2C=CC=C(F)C=2)=C(Cl)C=1)C1=C(C#N)C=NC2=CC(=C(C=C12)NC(=O)/C=C/CN(C)C)OCC
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| InChi Key |
NERXPXBELDBEPZ-RMKNXTFCSA-N
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| InChi Code |
InChI=1S/C31H29ClFN5O3/c1-4-40-29-16-26-24(15-27(29)37-30(39)9-6-12-38(2)3)31(21(17-34)18-35-26)36-23-10-11-28(25(32)14-23)41-19-20-7-5-8-22(33)13-20/h5-11,13-16,18H,4,12,19H2,1-3H3,(H,35,36)(H,37,39)/b9-6+
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| Chemical Name |
(E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
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| Synonyms |
HKI357 HKI 357
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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) |
DMSO : ~100 mg/mL (~174.20 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (4.36 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7420 mL | 8.7100 mL | 17.4201 mL | |
| 5 mM | 0.3484 mL | 1.7420 mL | 3.4840 mL | |
| 10 mM | 0.1742 mL | 0.8710 mL | 1.7420 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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