TY - JOUR
T1 - Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF
AU - Murphy, Eric A.
AU - Shields, David J.
AU - Stoletov, Konstantin
AU - Dneprovskaia, Elena
AU - McElroy, Michele
AU - Greenberg, Joshua I.
AU - Lindquist, Jeff
AU - Acevedo, Lisette M.
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.
AU - Arnold, Lee
AU - Wrasidlo, Wolfgang
AU - Cheresh, David A.
PY - 2010/3/2
Y1 - 2010/3/2
N2 - 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.
AB - 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.
KW - Cell-based screening
KW - Kinase inhibition
KW - Pancreatic carcinoma
KW - Pericyte
KW - Type II inhibitor
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U2 - 10.1073/pnas.0909299107
DO - 10.1073/pnas.0909299107
M3 - Article
C2 - 20154271
AN - SCOPUS:77749279762
SN - 0027-8424
VL - 107
SP - 4299
EP - 4304
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -