Cyclin-dependent kinases (Cdk) play crucial roles in cell cycle progression. Aberrant activation of Cdk1 has been observed in a number of primary tumors and Cdk2 is deregulated in various malignancies. The therapeutic value of targeting Cdk1 and Cdk2 has been explored in a number of experimental systems.
View Article and Find Full Text PDFIn this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors.
View Article and Find Full Text PDFThe TAM subfamily of Receptor Tyrosine Kinases (RTKs) contains three human proteins of therapeutical interest, Axl, Mer, and Tyro3. Our goal was to design a type II inhibitor specific for this family, i.e.
View Article and Find Full Text PDFAn efficient microwave-assisted palladium/copper comediated C-8 direct alkenylation of purines with styryl bromides has been developed. The method is regioselective, functional group tolerant, rapid, and compatible with other related azoles. Combined with subsequent nucleophilic substitution, it provides an easy access to new 6,8,9-trisubstituted purines.
View Article and Find Full Text PDFA series of 8-arylated purine derivatives bearing either an aniline or an alkyl amide at position 6 were found to inhibit glycogen synthase kinase-3, with good selectivity over ten kinases. Molecular modeling studies indicated that the most active compounds (8a and 8e), adopt a planar conformation, close to the shape of AMPPNP in the crystal structure of GSK-3. These compounds are stabilized by hydrophobic contacts between the 8-aromatic group and the protein adenine pocket and by electrostatic contacts.
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