Discovery and Optimization of 4‑Aminopteridin-7(8H)‑one Derivatives as Potent and Selective mTOR Inhibitors with Favorable Pharmacodynamic and Safety Characteristics

The
mechanistic target of rapamycin (mTOR) is a central
regulator
of cell growth and a promising cancer therapeutic target. Using structure-guided
design, we developed novel 4-aminopteridin-7(8H)-one
derivatives as ATP-competitive mTOR inhibitors. The lead compound
T133 (51) demonstrated exceptional mTOR inhibition (Ki = 0.17 nM) with high selectivity, effectively
suppressing phosphorylation of downstream effectors, such as AKT,
S6K1, and 4EBP1. In HGC-27 gastric cancer cells, T133 potently inhibited
proliferation and migration while inducing apoptosis, cell cycle arrest,
and autophagy. This efficacy extended to NCI-H1299 lung cancer and
T-47D breast cancer cells. In the HGC-27 xenograft mouse model, oral
administration of T133 exhibited dose-dependent efficacy comparable
to clinical-stage inhibitor PF-04691502, while exhibiting significantly
reduced hepatotoxicity, nephrotoxicity, and pulmonary toxicity. Moreover,
assessments of T133 on cytochrome P450, hERG, and AMES indicate a
favorable safety profile. These findings suggest T133 is a promising
mTOR inhibitor, warranting further investigation for cancer therapy.