Identification of novel aminopyrimidine derivatives as protein kinase inhibitors blocking cell growth.

Aminopyrimidine scaffold is typical of some of the most promising anticancer drug recently discovered thanks to their ability to inhibit different types of protein kinases. Kinase deregulation has emerged as a relevant mechanism by which cancer cells evade normal physiological constraints and kinases inhibitors have become one of the most intensively pursued classes of recent antitumoral drugs. Owing to the significance of pyrimidine derivatives as anticancer agents through kinase inhibition and our longstanding expertise in the development of pyrimidine derivatives, we designed and synthesized various classes of anilino and bis-anilinopyrimidines. Most of them were found active in in vitro HTRF inhibition assays in low nanomolar range against one or more kinases, like EGFR, c-KIT, VEGFR, PDGFR, Akt and AURKA, wild type or mutated and double-mutated isoforms. Some compounds were also crystallized in the active site of some kinases, showing a preference for DFG-in or DFG-out conformation. Subsequently, the antitumor activity of selected compounds was evaluated on three different human cancer types chosen on the basis of their unsatisfactory therapeutic strategies and poor prognosis: glioblastoma multiforme, triple-negative breast cancer, colon adenocarcinoma, tongue squamous carcinoma and hypopharyngeal squamous carcinoma. Various pyrimidines demonstrated to also hinder cell proliferation and cell cycle and to induce apoptosis in all the tested cell lines, without exerting cytotoxic effects at the same concentrations. The data coming from the biological assays will be shown and discussed.