Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl)nicotinonitrile scaffold
Copyright policy )Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl)nicotinonitrile scaffold
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.
- University of Milano-Bicocca Italy
- Universität Hamburg Germany
- Technische Universität Braunschweig Germany
Models, Molecular, Cell Line, Tumor, Nitriles, Proto-Oncogene Proteins c-ret, Antiproliferative activity; Cancer cell line; Enzyme inhibition; RET tyrosine kinase;, Molecular Conformation, Humans, Protein Kinase Inhibitors, Cell Proliferation
Models, Molecular, Cell Line, Tumor, Nitriles, Proto-Oncogene Proteins c-ret, Antiproliferative activity; Cancer cell line; Enzyme inhibition; RET tyrosine kinase;, Molecular Conformation, Humans, Protein Kinase Inhibitors, Cell Proliferation
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