Discovery and Optimization of 4-Aminopteridin-7(8 H)-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 (K_i = 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.