Novel small molecule inhibitors of c-terminal Src kinase [Csk]
Anna Y. Kilimnik, Maria N. Kostjukova, Ilya Pyatkin, A.M. Pronin, S.R. Strelnikowa, Y.A. Fedotov, Aleksandr Kolesnikov · 2003
Src-family kinases, a closely related group of nonreceptor tyrosine kinases play key role in eukaryotic signal transduction. The Src kinases are recognized as important targets for therapeutic interventions to treat cancer and immunological diseases. The specific aim of this work was to select new leads for development of ATPsite directed low molecular weight inhibitors of Src kinase family. A prototypic Src-like PTK, c-terminal Src kinase (Csk) was used as the model enzyme. About 2000 derivatives of s-triazolo[4,3-a]quinoline-1-thione, thieno[3,2-e][1,2,4]thiazolo[4,3-c]pyrimidine-3-thione, 2-thioxo-2,3-dihydro-1H-thieno[2,3-d]pyrimidin-4-one and [1,3,4]oxadiazole-2-thione were selected from ASINEX compound libraries, based on the initial in silico screening procedure. Compounds were filtered according to Lipinski’s “Rule of Five”[1]. All modeling studies were performed using the program Sybyl 6.8. Threedimensional structure of Csk was retrieved from the RCSB Protein data bank. The fast docking of ligands was generated using the program Flex X (Tripos