The aberrant activation of the Wnt signalling pathway is believed to be a major driving force in a broad range of pathological conditions and is common in many types of human tumors. Inhibition of the pathway has been shown to block tumor growth giving great therapeutic potential to drugs targeting this pathway. 1 In a program aimed at the identification of small molecules inhibitors of the Wnt pathway for the treatment of glioblastoma (GBM) we identify a series of aminopyridines which specifically inhibit the pathway without affecting cell viability. This series of compounds has been expanded with the synthesis of a focused set of aminopyrimidines with two points of diversity. All compounds have been tested for their activity on the Wnt pathway using DBTRG cells stably transfected with TCF-Luciferase and TA-Renilla. The TCF-Luc reporter gene specifically responds to Wnt stimuli while the Renilla readout is Wnt independent and can be used as cell viability readout. In addition, in order to identify potential ADME liabilities, all compounds were tested for their in vitro solubility, metabolic stability and permeability. (1) Barker, N.; Clevers, H. Nat. Rev. Drug Discov. 2006, 5, 997-1014.

Aminopyrimidines as inhibitors of the Wnt signalling pathway

DEL BELLO, FABIO;GIANNELLA, Mario;PIERGENTILI, Alessandro;QUAGLIA, Wilma;
2010

Abstract

The aberrant activation of the Wnt signalling pathway is believed to be a major driving force in a broad range of pathological conditions and is common in many types of human tumors. Inhibition of the pathway has been shown to block tumor growth giving great therapeutic potential to drugs targeting this pathway. 1 In a program aimed at the identification of small molecules inhibitors of the Wnt pathway for the treatment of glioblastoma (GBM) we identify a series of aminopyridines which specifically inhibit the pathway without affecting cell viability. This series of compounds has been expanded with the synthesis of a focused set of aminopyrimidines with two points of diversity. All compounds have been tested for their activity on the Wnt pathway using DBTRG cells stably transfected with TCF-Luciferase and TA-Renilla. The TCF-Luc reporter gene specifically responds to Wnt stimuli while the Renilla readout is Wnt independent and can be used as cell viability readout. In addition, in order to identify potential ADME liabilities, all compounds were tested for their in vitro solubility, metabolic stability and permeability. (1) Barker, N.; Clevers, H. Nat. Rev. Drug Discov. 2006, 5, 997-1014.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11581/336004
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