Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors.

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Pevet I, Brule C, Tizot A, Gohier A, Cruzalegui F, Boutin JA, Goldstein S

Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors.

Bioorg Med Chem. 2011 Apr 15;19(8):2517-28. doi: 10.1016/j.bmc.2011.03.021. Epub 2011 Mar 13.

PubMed ID

21459579 [ View in PubMed

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Abstract

Among the recently investigated targets for cancer therapy is the c-Src non-receptor tyrosine kinase. Indeed research around deregulated activity of this enzyme has proven its role in tumor progression, while the beneficial effects of c-Src inhibitors in several pathological models has also been demonstrated. We report here the preparation and pharmacological profile of a novel series of c-Src inhibitors that was elaborated around a 3-amino-thieno[2,3-b]pyridine discovered during an HTS campaign. c-Src enzyme inhibition and c-Src inhibition were investigated in a series of related compounds derived from the initial hit. Molecular modeling as well as X-ray studies on one active compound allowed us to hypothesize on ligand orientation and interactions within the ATP hydrophobic pocket. Design and synthesis of structural analogs then led to new ligands possessing quite efficient enzymatic and c-Src inhibition. The structure-activity elements disclosed in this study shed light on the role played by substituents on the thienopyridine ring as well as the impact of other aromatic moieties in the molecule when interacting with the enzyme.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bosutinib	Proto-oncogene tyrosine-protein kinase Src	IC 50 (nM)	1	N/A	N/A	Details
Dasatinib	Proto-oncogene tyrosine-protein kinase Src	IC 50 (nM)	0.6	N/A	N/A	Details