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

Eric A. Murphy, David J. Shields, Konstantin Stoletov, Elena Dneprovskaia, Michele McElroy, Joshua I. Greenberg, Jeff Lindquist, Lisette M. Acevedo, Sudarshan Anand, Bharat Kumar Majeti, Igor Tsigelny, Adrian Saldanha, Breda Walsh, Robert M. Hoffman, Michael Bouvet, Richard L. Klemke, Peter K. Vogt, Lee Arnold, Wolfgang Wrasidlo, David A. Cheresh

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 lackspecificityand/or functionpoorly in cellswhereATP 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 PDGFRβ and BRAF, 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) zebrafishembryogenesismodel.Dual inhibitionofPDGFRβ and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and murine models of angiogenesis, and a combination of previously characterized PDGFRβ 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.

Original languageEnglish (US)
Pages (from-to)4299-4304
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number9
DOIs
StatePublished - Mar 2 2010
Externally publishedYes

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Phosphotransferases
Growth
Pharmaceutical Preparations
Neoplasms
Adenosine Triphosphate
Allosteric Site
Pericytes
Triazoles
Zebrafish
Computer Simulation
Pancreas
Catalytic Domain
Cell Survival
Endothelial Cells
Pharmacokinetics
Neoplasm Metastasis
Kidney

Keywords

  • Cell-based screening
  • Kinase inhibition
  • Pancreatic carcinoma
  • Pericyte
  • Type II inhibitor

ASJC Scopus subject areas

  • General

Cite this

Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF. / Murphy, Eric A.; Shields, David J.; Stoletov, Konstantin; Dneprovskaia, Elena; McElroy, Michele; Greenberg, Joshua I.; Lindquist, Jeff; Acevedo, Lisette M.; Anand, Sudarshan; Majeti, Bharat Kumar; Tsigelny, Igor; Saldanha, Adrian; Walsh, Breda; Hoffman, Robert M.; Bouvet, Michael; Klemke, Richard L.; Vogt, Peter K.; Arnold, Lee; Wrasidlo, Wolfgang; Cheresh, David A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 9, 02.03.2010, p. 4299-4304.

Research output: Contribution to journalArticle

Murphy, EA, Shields, DJ, Stoletov, K, Dneprovskaia, E, McElroy, M, Greenberg, JI, Lindquist, J, Acevedo, LM, Anand, S, Majeti, BK, Tsigelny, I, Saldanha, A, Walsh, B, Hoffman, RM, Bouvet, M, Klemke, RL, Vogt, PK, Arnold, L, Wrasidlo, W & Cheresh, DA 2010, 'Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 9, pp. 4299-4304. https://doi.org/10.1073/pnas.0909299107
Murphy, Eric A. ; Shields, David J. ; Stoletov, Konstantin ; Dneprovskaia, Elena ; McElroy, Michele ; Greenberg, Joshua I. ; Lindquist, Jeff ; Acevedo, Lisette M. ; Anand, Sudarshan ; Majeti, Bharat Kumar ; Tsigelny, Igor ; Saldanha, Adrian ; Walsh, Breda ; Hoffman, Robert M. ; Bouvet, Michael ; Klemke, Richard L. ; Vogt, Peter K. ; Arnold, Lee ; Wrasidlo, Wolfgang ; Cheresh, David A. / Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 9. pp. 4299-4304.
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AU - Anand, Sudarshan

AU - Majeti, Bharat Kumar

AU - Tsigelny, Igor

AU - Saldanha, Adrian

AU - Walsh, Breda

AU - Hoffman, Robert M.

AU - Bouvet, Michael

AU - Klemke, Richard L.

AU - Vogt, Peter K.

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AU - Wrasidlo, Wolfgang

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