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

Abstract

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.

Discovery of wtRET and V804MRET Inhibitors: From Hit to Lead

“…Together, our results identified 69 as a multi cKIT/ wt RET/ V804M RET inhibitor. Notably, hit compound 1 was previously identified as a dual cKIT/PDGFRβ inhibitor (POC values <0.5 against both kinases under the same experimental conditions) . Hence, our efforts to improve activity against RET kinases also led to a slightly lower potency against PDGFRβ.…”

“…Compounds 22 and 23 were synthesized according to the same synthetic strategy as 5 (see Scheme ), with the only difference being the nature of arylboronic acid used in the first step. Compounds 24 and 25 were synthesized following our previously reported strategy . For the synthesis of compound 26 , the starting dichloropyrimidine was first converted into the 6‐amino‐4‐chloropyrimdine.…”

“…Substitution of the 6′′‐phenyl ring with heteroaryls resulted in similar potencies (compare 22 and 23 with 5 ). Conversely to what was previously observed for inhibition of class III receptor TK members, the introduction of a polar functionality at the 6′′‐phenyl ring decreased compound potency (see 24 ). The greatest effect was observed when a spacer was introduced between the pyrimidine and the aryl; the NH functionality led to a totally inactive compound ( 25 ), whereas a carboxamido functionality ( 26 ) furnished the most active compound overall.…”

“…As part of our kinase inhibitors discovery project, we recently reported that some N ‐phenyl‐ N ′‐[4‐(pyrimidin‐4‐ylamino)phenyl]urea derivatives behave as subfamily‐selective class III multitarget kinase inhibitors . To further investigate the usefulness of these compounds in developing novel TKIs, we tested compound 1 (selected as a hit compound in our previous study) against some kinases phylogenetically related to the class III receptor TKs, that is, the FGFR family and the kinase RET.…”

“…In this work, we report our efforts in the development of novel analogues of compound 1 endowed with sub‐micromolar RET inhibitory potency. According to our previous results, we hypothesized that 1 would bind the inactive kinase conformation. As no crystallographic structure has been deposited in the Protein Data Bank (PDB) to date for the inactive RET conformation, we decided to use a classical medicinal chemistry approach rather than a structure‐based approach.…”