HKI 357

Dual irreversible inhibitor of ErbB2 and EGFR CAS# 848133-17-5

HKI 357

Catalog No. BCC6046----Order now to get a substantial discount!

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Chemical structure

HKI 357

3D structure

Chemical Properties of HKI 357

Cas No. 848133-17-5 SDF Download SDF
PubChem ID 11238512 Appearance Powder
Formula C31H29ClFN5O3 M.Wt 574.05
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in DMSO and to 25 mM in ethanol
Chemical Name (E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
SMILES CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC(=CC=C4)F)Cl)C#N)NC(=O)C=CCN(C)C
Standard InChIKey NERXPXBELDBEPZ-RMKNXTFCSA-N
Standard InChI 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+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of HKI 357

DescriptionPotent, irreversible inhibitor of ErbB2 (HER2) and EGFR (IC50 values are 33 and 34 nM respectively). Suppresses ligand-induced EGFR autophosphorylation and cell proliferation in NCI-H1975 cells containing L858R and T790M mutations. Circumvents mechanisms of resistance to Iressa in non-small-cell lung cancer cells.

HKI 357 Dilution Calculator

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HKI 357 Molarity Calculator

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Preparing Stock Solutions of HKI 357

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.742 mL 8.71 mL 17.4201 mL 34.8402 mL 43.5502 mL
5 mM 0.3484 mL 1.742 mL 3.484 mL 6.968 mL 8.71 mL
10 mM 0.1742 mL 0.871 mL 1.742 mL 3.484 mL 4.355 mL
50 mM 0.0348 mL 0.1742 mL 0.3484 mL 0.6968 mL 0.871 mL
100 mM 0.0174 mL 0.0871 mL 0.1742 mL 0.3484 mL 0.4355 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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References on HKI 357

Pharmacology and signaling properties of epidermal growth factor receptor isoforms studied by bioluminescence resonance energy transfer.[Pubmed:16968809]

Mol Pharmacol. 2007 Feb;71(2):508-18.

We have developed a new assay for measuring epidermal growth factor receptor (EGFR) activation using the bioluminescence resonance energy transfer (BRET) technology, which directly measures the recruitment of signaling proteins to activated EGFR. Our results demonstrate that EGFR BRET assays precisely measure the pharmacology and signaling properties of EGFR expressed in human embryonic kidney 293T cells. EGFR BRET assays are highly sensitive to known EGFR ligands [pEC50 of epidermal growth factor (EGF)=10.1+/-0.09], consistent with previous pharmacological methods for measuring EGFR activation. We applied EGFR BRET assays to study the characteristics of somatic EGFR mutations that were recently identified in lung cancer. In agreement with recent reports, we detected constitutively active mutant EGFR isoforms, which predominantly signal through the phosphatidylinositol-3-kinase/Akt pathway. The EGFR inhibitors Iressa or Tarceva are severalfold more potent in inhibiting constitutive activity of mutant EGFR isoforms compared with wild-type EGFR. Notable, our results reveal that most of the mutant EGFR isoforms tested were significantly impaired in their response to EGF. The highest level of constitutive activity and nearly complete loss of epidermal growth factor responsiveness was detected in isoforms that carry the activating mutation L858R and the secondary resistance mutation T790M. In summary, our study reveals that somatic mutations in EGFR quantitatively differ in pharmacology and signaling properties, which suggest the possibility of differential clinical responsiveness to treatment with EGFR inhibitors. Furthermore, we demonstrate that the EGFR BRET assays are a useful tool to study the pharmacology of ligand-induced interaction between EGFR and signaling pathway-specifying adapter proteins.

Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib.[Pubmed:15897464]

Proc Natl Acad Sci U S A. 2005 May 24;102(21):7665-70.

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.

Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity.[Pubmed:15715478]

J Med Chem. 2005 Feb 24;48(4):1107-31.

A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

Description

HKI-357 is an irreversible dual inhibitor of EGFR and ERBB2 with IC50s of 34 nM and 33 nM, respectively. HKI-357 suppresses EGFR autophosphorylation (at Y1068), and AKT and MAPK phosphorylation.

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