ABSTRACT
The TAM (Axl, Mer, and Tyro3) family is implicated in the survival and chemoresistance of tumours and has emerged as a potential therapeutic target. A novel series of 7-aryl-2-anilino-pyrrolopyrimidines were identified as potent Axl/Mer tyrosine kinase inhibitors without significant inhibition of Tyro3. A representative compound 27 exhibited IC50 values of 2 nM and 16 nM for Mer and Axl, respectively, and considerable inhibition for Mer phosphorylation in cells. Docking studies suggested that the formation of a salt bridge between the nitrogen of the aniline moiety with ASP678 of the Mer kinase domain as well as an interaction with the hinge region that most kinase inhibitors have in common would be essential to retain activity. These results could provide useful information for finding promising inhibitors of Axl/Mer for the treatment of cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Amino Acid Sequence , Aniline Compounds/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Signal Transduction , Structure-Activity RelationshipABSTRACT
Transforming growth factor-ß activated kinase-1 (TAK1) is a potential therapeutic target for cancers and inflammatory diseases. We synthesized a series of novel imidazopyrazine derivatives, which were found to exhibit potent inhibitory effect against TAK1. Compound 22a, which possesses a good pharmacokinetic profile, showed excellent in vitro kinase activity and significant in vivo efficacy in mice xenografted with SW620, a KRAS-dependent colon cancer cell line.
