New 2-alkoxycyanopyridine derivatives as inhibitors of EGFR, HER2, and DHFR: Synthesis, anticancer evaluation, and molecular modeling studies.

New series of substituted 2-alkoxycyanopyridine derivatives were synthesized and evaluated for their in vitro and in vivo anticancer activities. Comparing the evaluated activities against cancer cell lines to the broad-spectrum anticancer doxorubicin, and the kinase inhibitor sorafenib, compounds 3a, 4b, 4c, 7a, and 8d demonstrated superior anticancer efficacy with elevated safety profiles and selectivity indices, particularly against MCF7 breast cancer. For exploration of their mechanism of action, assays for inhibition of EGFR, HER2 kinase, and DHFR were performed.