Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of Type III receptor tyrosine kinase subfamily

Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi-target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis the kinase profiling and the biological evaluation of a set of novel 4-anilinopyrimidines as promising anticancer compounds. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds. Among synthesized compounds, N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives targeted some members of type III receptor tyrosine kinase family. In particular, compound 24 was identified as a selective dual KIT/PDGFRbeta inhibitor. The compound was more cytotoxic than sunitinib against A549 and PxPC3 human cancer cell lines, and showed a preferential antiproliferative activity toward neoplastic rather than HEK293 non-tumor cells. Overall, our data suggested that the 4-anilino-6-phenylpyrimidines constitute a promising class of subfamily selective inhibitors of Type III RTKs subfamily. These results are of remarkably importance since, despite the huge interest in identifying subfamily selective kinase inhibitors, poorly toxic and highly active as antitumor agents, nowadays there is still a paucity of reports investigating their antitumor activity.