Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities - Part 1

Overexpression of EGFR and HER2 are observed in many breast, ovarian, colon and prostate cancers. The second and third generation irreversible EGFR/HER2 dual kinase inhibitors became popular after the approval of Afatinib by FDA to overcome the mutation related problem. To find efficacious drug candidates, a series of novel quinazoline derivatives were designed, synthesized and evaluated as dual EGFR/HER2 tyrosine kinase (TK) inhibitors. Selected twenty four compounds were reported here with significant inhibitory activities against EGFR/HER2 tyrosine kinases. Several compounds showed nanomolar IC₅₀ values. In vitro studies of quinazoline derivatives were done on NCI-H1975, HCC827, A431, MDA MB-453 cell lines. The compounds 1a, 1d and 1v were found more potent compared to standard drug afatinib. In vivo efficacy study of 1d on nude mice NCI-H1975 tumour xenograft model was discussed.

Anticancer; Antitumor; Dual inhibitor; EGFR; HER2; Irreversible; Quinazoline; Tyrosine kinase.