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 (13g) 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. © 2010 Elsevier Masson SAS.