Built upon the 4-acrylamido quinoline derivative 4, a previously discovered PI3K/mTOR dual inhibitor, structural modification was undertaken in this study with the attempt to improve its oral exposure via introducing steric hindrance to the 4-acrylamido functionality. Consequently, 14d, as the representative among the synthesized compounds, exhibited IC50 values of 0.80, 0.67, 1.30, 1.30 and 5.0 nM against PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and mTOR, respectively. Besides, 14d displayed comparable anti-proliferative activity against both PC3 and U87MG cell lines to that of the positive reference GSK2126458 with respective GI50 value of 0.36 and 0.14 μM. Kinase selectivity assay showed that 14d was selective to PI3K family. In U87MG cells, 14d can strongly down-regulate PI3K/Akt/mTOR pathway via blocking both PI3K and mTOR signaling at the concentration as low as 25 nM. Importantly, following a PO dose of 5 mg/kg in male SD rats, 14d displayed favorable oral exposure (AUC0-t = 1336.16 h × ng/mL, AUC0-∞ = 1447.63 h × ng/mL) and high maximum plasma concentration (Cmax = 903.00 ng/mL). In a U87MG glioblastoma xenograft model, tumor growth inhibition of 93.5% and tumor regression were observed at PO dose of 30 and 60 mg/kg, respectively. Meanwhile, no overt loss of body weight was observed in the 14d-treated groups. Taken together, 14d, by virtue of its attractive performance, merits further development as a potential anti-tumor candidate.
Keywords: Cancer; PI3K; PI3K/mTOR dual inhibitor; Quinoline derivatives; mTOR.
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