Highly Selective, Potent, and Oral mTOR Inhibitor for Treatment of Cancer as Autophagy Inducer

On the basis of novel pyrazino­[2,3-c]­quinolin-2­(1H)-one scaffold, we designed
and identified a highly selective, potent and oral mTOR inhibitor, 9m. Compound 9m showed low nanomolar activity
against mTOR (IC50 = 7 nM) and greater selectivity over
the related PIKK family kinases, which demonstrated only modest activity
against 3 out of the 409 protein kinases. In vitro assays, compound 9m exhibited high potency against human
breast and cervical cancer cells and induced tumor cell cycle arrest
and autophagy. 9m inhibited cellular phosphorylation
of mTORC1 (pS6 and p4E-BP1) and mTORC2 (pAKT (S473)) substrates. In
T-47D xenograft mouse model, oral administration of compound 9m led to significant tumor regression without obvious toxicity.
In addition, this compound showed good pharmacokinetics. Collectively,
due to its high potency and selectivity, compound 9m could
be used as a mTOR drug candidate.