Skip to main content
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

  • Register
  • Log in
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
    • CME
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in

Search

  • Advanced search
Clinical Cancer Research
Clinical Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
    • CME
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
Cancer Therapy: Preclinical

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Rabia A. Gilani, Sameer Phadke, Li Wei Bao, Eric J. Lachacz, Michele L. Dziubinski, Kristoffer R. Brandvold, Michael E. Steffey, Frank E. Kwarcinski, Carrie R. Graveel, Kelley M. Kidwell, Sofia D. Merajver and Matthew B. Soellner
Rabia A. Gilani
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sameer Phadke
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Li Wei Bao
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric J. Lachacz
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michele L. Dziubinski
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kristoffer R. Brandvold
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael E. Steffey
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frank E. Kwarcinski
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carrie R. Graveel
Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kelley M. Kidwell
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sofia D. Merajver
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: soellner@med.umich.edusmerajve@med.umich.edu
Matthew B. Soellner
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: soellner@med.umich.edusmerajve@med.umich.edu
DOI: 10.1158/1078-0432.CCR-15-2158
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.

Experimental Design: We have analyzed the anti–triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts.

Results: We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.

Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 1–10. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received September 9, 2015.
  • Revision received March 25, 2016.
  • Accepted April 16, 2016.
  • ©2016 American Association for Cancer Research.
Next
Back to top

Published OnlineFirst September 2, 2016
doi: 10.1158/1078-0432.CCR-15-2158

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Clinical Cancer Research 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.
UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer
(Your Name) has forwarded a page to you from Clinical Cancer Research
(Your Name) thought you would be interested in this article in Clinical Cancer Research.
Citation Tools
UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer
Rabia A. Gilani, Sameer Phadke, Li Wei Bao, Eric J. Lachacz, Michele L. Dziubinski, Kristoffer R. Brandvold, Michael E. Steffey, Frank E. Kwarcinski, Carrie R. Graveel, Kelley M. Kidwell, Sofia D. Merajver and Matthew B. Soellner
Clin Cancer Res September 2 2016 DOI: 10.1158/1078-0432.CCR-15-2158

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer
Rabia A. Gilani, Sameer Phadke, Li Wei Bao, Eric J. Lachacz, Michele L. Dziubinski, Kristoffer R. Brandvold, Michael E. Steffey, Frank E. Kwarcinski, Carrie R. Graveel, Kelley M. Kidwell, Sofia D. Merajver and Matthew B. Soellner
Clin Cancer Res September 2 2016 DOI: 10.1158/1078-0432.CCR-15-2158
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Radiotherapy with IDO1/PD-1 Blockade Treats Advanced GBM
  • TCRs against MCV T-antigens
  • B7-H3 Negatively Modulates Cancer Immunity
Show more Cancer Therapy: Preclinical
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • CCR Focus Archive
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Clinical Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2018 by the American Association for Cancer Research.

Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

Advertisement