Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl)nicotinonitrile scaffold.

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Brandt W, Mologni L, Preu L, Lemcke T, Gambacorti-Passerini C, Kunick C

Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl)nicotinonitrile scaffold.

Eur J Med Chem. 2010 Jul;45(7):2919-27. doi: 10.1016/j.ejmech.2010.03.017. Epub 2010 Mar 19.

PubMed ID

20409618 [ View in PubMed

]

Abstract

In an approach to optimize 2-(4-fluorobenzylsulfanyl)-4-(2-thienyl)-5,6,7,8-tetrahydroquinoline-3-carbonitri le (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-dic arbonitrile (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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Proto-oncogene tyrosine-protein kinase receptor Ret	P07949	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Vandetanib	Proto-oncogene tyrosine-protein kinase receptor Ret	IC 50 (nM)	97	N/A	N/A	Details