Discovery of 2‑Methyl-2-(4-(2-methyl-8-(1<i>H</i>‑pyrrolo[2,3‑<i>b</i>]pyridin-6-yl)‑1<i>H</i>‑naphtho[1,2‑<i>d</i>]imidazol-1-yl)phenyl)propanenitrile as a Novel PI3K/mTOR Inhibitor with Enhanced Antitumor Efficacy <i>In Vitro</i> and <i>In Vivo</i>

PI3K/Akt/mTOR signaling pathway is a validated drug target for cancer treatment that plays a critical role in controlling tumor growth, proliferation, and apoptosis. However, no FDA-approved PI3K/mTOR dual inhibitor exists. Thus, a candidate with a better curative effect and lower toxicity is still urgently needed. Herein, we design, synthesize, and evaluate compounds belonging to a novel series of 2-methyl-1H-imidazo­[4,5-c]­quinoline scaffold derivatives as PI3K/mTOR dual inhibitors. Among them, compound 8o was identified as a novel candidate with excellent kinase selectivity. It manifested remarkable antiproliferative activities against SW620 and HeLa cells. Western blot and immunohistochemical analysis results proved that 8o could regulate the PI3K/AKT/mTOR signaling pathway by inhibiting the phosphorylation of AKT and S6 proteins. Additionally, 8o presented a favorable pharmacokinetic property (oral bioavailability of 76.8%) and significant antitumor efficacy in vivo without obvious toxicity. Collectively, these results indicated that 8o is a promising agent for cancer treatment and merits further development.