HKI-357 (HKI357) is a novel and potent dual inhibitor of EGFR and ERBB2 that irreversibly inhibits EGFR and ERBB2 with IC50s of 34 nM and 33 nM, respectively. HKI-357 suppresses EGFR autophosphorylation (at Y1068), and AKT and MAPK phosphorylation.
Physicochemical Properties
| Molecular Formula | C₃₁H₂₉CLFN₅O₃ |
| Molecular Weight | 574.05 |
| Exact Mass | 573.194 |
| Elemental Analysis | C, 64.86; H, 5.09; Cl, 6.18; F, 3.31; N, 12.20; O, 8.36 |
| CAS # | 848133-17-5 |
| Related CAS # | 848133-17-5;915942-25-5; |
| PubChem CID | 11238512 |
| Appearance | Off-white to yellow solid powder |
| LogP | 6.747 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 11 |
| Heavy Atom Count | 41 |
| Complexity | 915 |
| Defined Atom Stereocenter Count | 0 |
| 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 |
| InChi Key | NERXPXBELDBEPZ-RMKNXTFCSA-N |
| 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+ |
| Chemical Name | (E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide |
| Synonyms | HKI357 HKI 357 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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]. |
| 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. |
| References |
[1]. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7665-70. |
| Additional Infomation | Hki 357 is under investigation in clinical trial NCT00550381 (Study Evaluating the Safety, Tolerability, and Pharmacokinetics (PK) of HKI-357 Administered Orally to Healthy Subjects). |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~174.20 mM) |
| 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |