title: Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl)nicotinonitrile scaffold.
abstract: In an approach to optimize 2-(4-fluorobenzylsulfanyl)-4-(2-thienyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (1a), a weak inhibitor of the cancer-related tyrosine kinase RET originating from a screening campaign, analogues with 3-thienyl substitution were prepared. Among the novel derivatives, 2-amino-6-{[2-(4-chlorophenyl)-2-oxoethyl]sulfanyl}-4-(3-thienyl)pyridine-3,5-dicarbonitrile (13 g) was identified as a submicromolar RET inhibitor, displaying 3- and 100-fold selectivity versus ALK and ABL kinases, respectively. The novel inhibitor exhibited antiproliferative activity in the micromolar concentration range against both RET-dependent and RET-independent cancer cell lines. Docking experiments suggest a binding mode of the new inhibitors in the ATP binding pocket of the target kinase, explaining the observed structure-activity relationships.
authors.affiliation: Technische Universität Braunschweig, Institut für Pharmazeutische Chemie, Beethovenstrasse 55, D-38106 Braunschweig, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Brandt
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
authors.forename: Lutz
authors.initials: L
authors.lastname: Preu
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemcke
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret