Imidazo[1,2-a]quinoxalines for melanoma treatment with original mechanism of action

The malignant transformation of melanocytes causes several thousand deaths each year, making melanoma an important public health concern. Melanoma is the most aggressive skin cancer, which incidence has regularly increased over past decades. We described here preparation new compounds based on 1-(3,4-dihydroxyphenyl)imidazo[1,2-a]quinoxaline structure. Different positions quinoxaline moiety were screened to introduce novel substituents in order study their influence biological activity. Several alkylamino or alkyloxy groups also considered replace methylamine our first generation Imiqualines. Imidazo[1,2-a]pyrazine derivatives designed as potential minimal investigation A375 cells displayed interesting vitro low nanomolar cytotoxic Among them, 9d (EAPB02303) particularly remarkable since it 20 times more potent than vemurafenib, reference clinical therapy used BRAF mutant melanoma. Contrary generation, EAPB02303 does not inhibit tubulin polymerization, confirmed by assay and a molecular modelisation study. mechanism action for highlighted transcriptomic analysis clearly different from panel 12 well-known anticancer drugs. In vivo treatment reduced tumor size weight human xenografts dose-dependent manner, correlated with mitotic index but necrosis.