title: Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors.
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.
authors.affiliation: Bristol-Myers Squibb, Oncology Drug Discovery, Princeton, NJ 08543, USA. stuart.emanuel@bms.com
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Emanuel
authors.forename: Terry V
authors.initials: TV
authors.lastname: Hughes
authors.forename: Mary
authors.initials: M
authors.lastname: Adams
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Rugg
authors.forename: Angel
authors.initials: A
authors.lastname: Fuentes-Pesquera
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Connolly
authors.forename: Niranjan
authors.initials: N
authors.lastname: Pandey
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno-Mazza
authors.forename: Jeannene
authors.initials: J
authors.lastname: Butler
authors.forename: Virna
authors.initials: V
authors.lastname: Borowski
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gruninger
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Story
authors.forename: Cheryl
authors.initials: C
authors.lastname: Napier
authors.forename: Beth
authors.initials: B
authors.lastname: Hollister
authors.forename: Lee M
authors.initials: LM
authors.lastname: Greenberger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000201:enzymology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009025:Morpholines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D009025:Morpholines; D011743:Pyrimidines; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C526582:JNJ 28871063; C512478:EGFR protein, human; C508053:ERBB2 protein, human