Mieshkova N. Antitumour activity and mechanisms of action or new quinazoline derivatives

On a basis of virtual screening there were chosen new quinazoline derivatives and known quinazoline-based hypotensive drugs with ?1-adrenoblocking activity (Prazosin, Doxazosin, Terazosin, Alfuzosin) and reference drug Erlotinib, which were predicted to have possible anticancer activity. Docking analysis showed that inhibitor-EGFR binding energy values of the some substances are higher than test of significance (-27,977 kcal/mol) on tyrosine kinases (1M17, 2ITY, 2GS2). It was shown that all quinazoline derivatives have some ?1-adrenoblocking activity (may cause dilatation of isolated blood vessel of rat - mesenteric artery, aorta, portal vein). Some substances have log(IC50) similar or higher or than Tarceva's (MTT assay). On a clinical material of human non-smallcell lung cancer (xenografts, subrenal capsule assay) it was showed possible different activity of quinazoline derivatives (Erlotinib, agent 3105): from high - 3105 - 52,05 % of tumour growth inhibition to the absence of growth inhibition. This fact enhances importance of the anterior evaluation of the individual sensitivity. It was shown that the main role in the mechanisms of quinazolines antitumour activity belongs to intensity of phosphotyrosine formation in EGFR. As this agent forms mitogenic signal cascade of EGFR (decrease of living cell quantity with the addition of tyrphostin, Erlotinib, agent 3105, decrease of fluoriscence of phosphotyrosine with the addition of Erlotinib and agent 3105 with phosphotyrosin antibodies binding).