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Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF

Academic Article
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Overview

authors

  • Murphy, E. A.
  • Shields, D. J.
  • Stoletov, K.
  • Dneprovskaia, E.
  • McElroy, M.
  • Greenberg, J. I.
  • Lindquist, J.
  • Acevedo, L. M.
  • Anand, S.
  • Majeti, B. K.
  • Tsigelny, I.
  • Saldanha, A.
  • Walsh, B.
  • Hoffman, R. M.
  • Bouvet, M.
  • Klemke, R. L.
  • Vogt, Peter K.
  • Arnold, L.
  • Wrasidlo, W.
  • Cheresh, D. A.

publication date

  • March 2010

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, and several kinase inhibitors are now approved for various cancer indications. Typically, kinase inhibitors are selected via high-throughput screening using catalytic kinase domains at low ATP concentration, and this process often yields ATP mimetics that lack specificity and/or function poorly in cells where ATP levels are high. Molecules targeting the allosteric site in the inactive kinase conformation (type II inhibitors) provide an alternative for developing selective inhibitors that are physiologically active. By applying a rational design approach using a constrained amino-triazole scaffold predicted to stabilize kinases in the inactive state, we generated a series of selective type II inhibitors of PDGFRbeta and B-RAF, important targets for pericyte recruitment and endothelial cell survival, respectively. These molecules were designed in silico and screened for antivascular activity in both cell-based models and a Tg(fli1-EGFP) zebrafish embryogenesis model. Dual inhibition of PDGFRbeta and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and murine models of angiogenesis, and a combination of previously characterized PDGFRbeta and RAF inhibitors validated the synergy. Our lead compound was selected as an orally active molecule with favorable pharmacokinetic properties which demonstrated target inhibition in vivo leading to suppression of murine orthotopic tumors in both the kidney and pancreas.

subject areas

  • Administration, Oral
  • Angiogenesis Inhibitors
  • Animals
  • Carcinoma, Renal Cell
  • Cell Division
  • Kidney Neoplasms
  • Neovascularization, Pathologic
  • Pancreatic Neoplasms
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Receptor, Platelet-Derived Growth Factor beta
  • Zebrafish
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Research

keywords

  • cell-based screening
  • kinase inhibition
  • pancreatic carcinoma
  • pericyte
  • type II inhibitor
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Identity

PubMed Central ID

  • PMC2840076

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0909299107

PubMed ID

  • 20154271
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Additional Document Info

start page

  • 4299

end page

  • 4304

volume

  • 107

issue

  • 9

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