Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors

Dysfunctional
signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role
in cell growth and survival have made it a much desired target for
cancer therapeutics. A series of dimorpholine substituted thienopyrimidine
derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor,
which had an approximately 8-fold improvement in mTOR inhibition relative
to the class I PI3K inhibitor 1 (pictilisib, GDC-0941).
Western blot analysis confirmed the 14o mechanistic modulation
of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation
of both AKT and S6 in human cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG
tumor xenograft models without causing significant weight loss and
toxicity.