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.
Highlights
The high number of FDA approved drugs in the last 15 years reveals the growing interest in TK inhibitors (TKIs)[15,16]
TKIs are commonly constituted by i) a nitrogen containing heterocycle able to form an H-bond with the hinge region; ii) an hydrophobic moiety interacting with the hydrophobic region I of the kinase; iii) a spacer between the heterocycle and the hydrophobic moiety (Fig. 1d,e)[15,22]
We have recently reported that the m-biphenylamine as aniline moiety led to multi kinase inhibitors targeting EGFR, fibroblast growth factor receptor-1 (FGFR1), VEGFR2, PDGFRβ, Src and Abl at nanomolar concentrations[34,35]
Summary
The high number of FDA approved drugs in the last 15 years reveals the growing interest in TK inhibitors (TKIs)[15,16]. Cancer is a multi factorial disease and recent findings have highlighted the importance of multi targeting compounds, i.e. compounds able to inhibit, with comparable potencies, more than one TK18 Both selective (e.g. erlotinib and gefitinib) and unselective (e.g. sunitinib and dasatinib) kinase inhibitors are useful anticancer drugs. The rational design of “selectively nonselective” TKIs is a challenging and fascinating goal: the ATP binding pocket is quite conserved in the entire kinome, and it is conserved inside each PKs subfamily. In this view, an achievable and promising aim could be the design/development of subfamily selective kinase inhibitors. In most cases the pyrimidine nucleus is not the main “nitrogen containing heterocycle”, since it does not interact with the hinge region, as shown by X-ray crystallography[29]
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