title: Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors.
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.
authors: Institut de Recherches Servier, Suresnes, France.
authors: Isabelle
authors: I
authors: Pevet
authors: Cédric
authors: C
authors: Brulé
authors: André
authors: A
authors: Tizot
authors: Arnaud
authors: A
authors: Gohier
authors: Francisco
authors: F
authors: Cruzalegui
authors: Jean A
authors: JA
authors: Boutin
authors: Solo
authors: S
authors: Goldstein
mesh_terms: D000255:Adenosine Triphosphate; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; C446540:thienopyridine; D000255:Adenosine Triphosphate; D019061:src-Family Kinases