Abstract |
JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab ( Herceptin) and cetuximab ( Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.
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Authors | Stuart L Emanuel, Terry V Hughes, Mary Adams, Catherine A Rugg, Angel Fuentes-Pesquera, Peter J Connolly, Niranjan Pandey, Sandra Moreno-Mazza, Jeannene Butler, Virna Borowski, Steven A Middleton, Robert H Gruninger, Jennifer R Story, Cheryl Napier, Beth Hollister, Lee M Greenberger |
Journal | Molecular pharmacology
(Mol Pharmacol)
Vol. 73
Issue 2
Pg. 338-48
(Feb 2008)
ISSN: 1521-0111 [Electronic] United States |
PMID | 17975007
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Antineoplastic Agents
- Enzyme Inhibitors
- JNJ 28871063
- Morpholines
- Pyrimidines
- Quinazolines
- EGFR protein, human
- ERBB2 protein, human
- ErbB Receptors
- Receptor Protein-Tyrosine Kinases
- Receptor, ErbB-2
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Topics |
- Animals
- Antineoplastic Agents
(chemistry, pharmacology, therapeutic use)
- Blood-Brain Barrier
(drug effects, enzymology)
- Brain Neoplasms
(drug therapy, enzymology)
- Cell Line, Tumor
- Enzyme Inhibitors
(chemistry, pharmacology, therapeutic use)
- ErbB Receptors
(antagonists & inhibitors, metabolism)
- Humans
- Mice
- Mice, Nude
- Mice, SCID
- Morpholines
(chemistry, pharmacology, therapeutic use)
- Pyrimidines
(chemistry, pharmacology, therapeutic use)
- Quinazolines
(chemistry, pharmacology, therapeutic use)
- Receptor Protein-Tyrosine Kinases
(antagonists & inhibitors, metabolism)
- Receptor, ErbB-2
(antagonists & inhibitors, metabolism)
- Xenograft Model Antitumor Assays
(methods)
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