Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleDrug Discovery and Translational Medicine

Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families

Keith B. Glaser, Junling Li, Patrick A. Marcotte, Terrance J. Magoc, Jun Guo, David R. Reuter, Paul Tapang, Ru-Qi Wei, Lori J. Pease, Mai H. Bui, Zehan Chen, Robin R. Frey, Eric F. Johnson, Donald J. Osterling, Amanda M. Olson, Jennifer J. Bouska, Yanping Luo, Michael L. Curtin, Cherrie K. Donawho, Michael R. Michaelides, Chris Tse, Steven K. Davidsen and Daniel H. Albert
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 617-627; DOI: https://doi.org/10.1124/jpet.112.197087
Keith B. Glaser
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Junling Li
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patrick A. Marcotte
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terrance J. Magoc
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jun Guo
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David R. Reuter
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Tapang
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ru-Qi Wei
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lori J. Pease
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mai H. Bui
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zehan Chen
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robin R. Frey
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric F. Johnson
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donald J. Osterling
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amanda M. Olson
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jennifer J. Bouska
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yanping Luo
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael L. Curtin
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cherrie K. Donawho
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael R. Michaelides
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chris Tse
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven K. Davidsen
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel H. Albert
Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC50) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC50 = 0.3–21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (Ki < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC50 ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.197087.

  • ABBREVIATIONS:

    VEGF
    vascular endothelial growth factor
    VEGFR
    VEGF receptor
    PDGF
    platelet-derived growth factor
    PDGFR
    PDGF receptor
    ALL
    acute lymphoblastic leukemia
    AML
    acute myeloid leukemia
    CML
    chronic myeloid leukemia
    CSF-1R
    colony-stimulating factor 1 receptor
    DCE-MRI
    dynamic contrast-enhanced magnetic resonance imaging
    ELISA
    enzyme-linked immunosorbent assay
    ABT-348
    1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea
    ABT-869
    1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea
    A-993352
    4-amino-N-(3-((3-(4-chloro-2-fluorophenyl)ureido)methyl)phenyl)thieno[2,3-d]pyrimidine-5-carboxamide
    AZD1152
    barasertib
    PHA-739358
    danusertib
    PPHA-739358
    (R)-N-(5-(2-methoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide
    ENMD-2076
    (E)-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine
    R763
    (1S,2S,3R,4R)-3-((5-fluoro-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide
    APC
    allophycocyanin
    HUVEC
    human umbilical vein endothelial cells
    DMSO
    dimethyl sulfoxide
    MDR
    multidrug resistance protein
    NSCLC
    non–small-cell lung carcinoma
    PBS
    phosphate-buffered saline
    KIT
    mast/stem cell growth factor receptor
    FBS
    fetal bovine serum
    PLGF
    placental growth factor
    MWF
    Monday, Wednesday, Friday
    FLT
    fms-like tyrosine kinase.

  • Received May 31, 2012.
  • Accepted August 21, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleDrug Discovery and Translational Medicine

Preclinical Characterization of the Kinase Inhibitor ABT-348

Keith B. Glaser, Junling Li, Patrick A. Marcotte, Terrance J. Magoc, Jun Guo, David R. Reuter, Paul Tapang, Ru-Qi Wei, Lori J. Pease, Mai H. Bui, Zehan Chen, Robin R. Frey, Eric F. Johnson, Donald J. Osterling, Amanda M. Olson, Jennifer J. Bouska, Yanping Luo, Michael L. Curtin, Cherrie K. Donawho, Michael R. Michaelides, Chris Tse, Steven K. Davidsen and Daniel H. Albert
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 617-627; DOI: https://doi.org/10.1124/jpet.112.197087

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleDrug Discovery and Translational Medicine

Preclinical Characterization of the Kinase Inhibitor ABT-348

Keith B. Glaser, Junling Li, Patrick A. Marcotte, Terrance J. Magoc, Jun Guo, David R. Reuter, Paul Tapang, Ru-Qi Wei, Lori J. Pease, Mai H. Bui, Zehan Chen, Robin R. Frey, Eric F. Johnson, Donald J. Osterling, Amanda M. Olson, Jennifer J. Bouska, Yanping Luo, Michael L. Curtin, Cherrie K. Donawho, Michael R. Michaelides, Chris Tse, Steven K. Davidsen and Daniel H. Albert
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 617-627; DOI: https://doi.org/10.1124/jpet.112.197087
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Methods and Materials
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • TRPA1 inhibitors ameliorate tear gas-induced skin injuries
  • Treatment of SM Corneal Injury by Augmenting the DDR
  • Symptomatic reversal of botulism by aminopyridines
Show more Drug Discovery and Translational Medicine

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics