Targeting tyrosine kinases: anti-proliferative and anti-angiogenic properties of 4-anilinoquinazolines

Inhibition of Tyrosine Kinases (TKs) blocks multiple intracellular signaling pathways involved in tumor growth, progression and angiogenesis. Therefore, the development of small ATP-mimetic Tyrosine Kinase Inhibitors (TKIs) resulted very attractive as anti-tumoral and anti-angiogenic tools. A major goal in the field of TKIs development is to find compounds able to inhibit more than one TK, in order to overcome the drug resistance onset. In this way, the blockade of several signaling pathways involved in tumor growth, as EGFR and VEGFR, has a strong rationale for development of multi-targeted TKIs. Several 4-anilinoquinazolines derivatives have been synthesized. The compounds have been submitted to specific biological assay on a panel of six different TKs and on tumor cell lines. The most active compounds were submitted to other biological evaluations in order to investigate the mechanism of action. The title derivatives induced cell death through activation of the pro-apoptotic pathway. Almost all the compounds showed very interesting anti-angiogenic activity. The effect on cell growth and cell migration induced was also evaluated in Human Umbilical Vein Endothelial Cells (HUVEC).