A research team led by Prof. TANG Shibing from the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences (CAS), has developed a new class of mammalian target of rapamycin (mTOR) inhibitors. The study was recently published in Journal of Medicinal Chemistry.

The mTOR signaling pathway serves as a central hub regulating cell growth, proliferation, and survival. Its abnormal activation is closely linked to the development and progression of various cancers, including gastric cancer, lung cancer, and breast cancer—making it a critical target for anticancer drug development. However, currently available mTOR inhibitors on the market remain highly limited, with the vast majority of candidate drugs failing in clinical development due to insufficient potency, excessive toxicity, or severe side effects.

To address these challenges, the team developed a series of 4-aminopteridin-7(8H)-one derivatives as ATP-competitive mTOR inhibitors through rational drug design. Among these compounds, the lead candidate T133 (compound 51) demonstrated particularly outstanding performance. Through structure-activity relationship studies and molecular simulations, the study revealed that the hydroxylated benzofuran and trans-cyclohexanecarboxylic acid moieties in the T133 molecule confer high affinity (IC50 = 0.34 nM) and excellent kinase selectivity by forming specific hydrogen bonds and salt-bridge interactions with mTOR.

Cellular experiments showed that T133 effectively inhibited cell proliferation and migration across multiple cancer cell lines, including those of gastric, lung, and breast cancer. Mechanistic studies further confirmed that T133 blocks the downstream mTOR signaling pathway, reducing the phosphorylation levels of key signaling proteins such as AKT, S6K1, and 4EBP1. This, in turn, induces tumor cell apoptosis, cell cycle arrest, and autophagy.

In a HGC-27 gastric cancer cell xenograft model, oral administration of T133 exhibited dose-dependent tumor-inhibitory effects: tumor inhibition rates reached 83% and 92% at doses of 30 mg/kg and 60 mg/kg, respectively. Its efficacy was comparable to that of PF-04691502, a clinically investigated inhibitor, while T133 showed significant safety advantages.

Unlike PF-04691502, which caused liver damage, lung injury, skin toxicity, and other adverse effects consistent with clinical reports, mice treated with T133 showed no significant pathological damage to vital organs, and their physiological and biochemical indicators remained stable. Furthermore, the drug's broad-spectrum anticancer activity was validated in the NCI-H1299 lung cancer model.

In terms of druggability, T133 exhibits good oral bioavailability (31.2%), weakly inhibits major drug-metabolizing enzymes (CYP450), has no potential cardiotoxicity (extremely low hERG inhibition), and is non-genotoxic (negative in the AMES test)—indicating an overall low risk for drug development.

This study offers new hope for overcoming the challenges in developing second-generation mTOR inhibitors. The work was supported by the CAS Strategic Priority Research Program, the Guangdong Basic and Applied Basic Research Foundation, and other funding sources.