FB-Qsar based developement of novel potent Tyrosine-Kinase Inhibitors

One of the most promising anticancer strategy is based on the use of small ATP-mimetic inhibitors. In the last few years, particular attention was given to 4-anilinoquinazoline derivatives, such as Erlotinib or PD153035 for their highly specific and potent antitumoral activity as tyrosine kinase inhibitors [1,2]. Recently , we have developed a novel synthetic strategy to 4-anilinoquinazoline [3-5] and synthesized novel promising compounds with very interesting citotoxic activity. The effect on cell growth induced by all the synthesized compounds was evaluated in both human squamous carcinoma cells (A431) and mouse embryonic fibroblasts (NIH3T3) expressing EGFR at various levels. Biological data were compared with those obtained using PD153035. Thus, starting from biological results, we evaluated several Fragment Based QSAR (FB-QSAR) approaches [6] to explain biological features of our compounds and we used our models to predict activity of novel derivatives. In particular, we found that replacement of aniline moiety with m-biphenyl could lead to very interesting citotoxic activity. Synthesis and biological evaluation of designed compounds revealed the validity of our models.