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 and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.

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Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non‐small‐cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild‐type RET (wtRET) and its mutants (e.g., V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub‐micromolar wtRET/V804MRET inhibitor, N‐(2‐fluoro‐5‐trifluoromethylphenyl)‐N′‐{4′‐[(2′′‐benzamido)pyridin‐4′′‐ylamino]phenyl}urea (69), endowed with a 4‐anilinopyridine structure, starting from our previously identified 4‐anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wtRET/V804MRET inhibitor.