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

  • J Med Chem. 2026 Feb 26;69(4):4829-4854. doi: 10.1021/acs.jmedchem.5c03503.
Danyang Wang  1 ,  Gengwu Li  1  2 ,  Jianguang Liu  1 ,  Mengxin Li  1 ,  Xudan Peng  1 ,  Jinfeng Deng  1 ,  Shujie Zhao  1 ,  Kang Zou  1 ,  Xiaohan Zhang  1 ,  Dan Liu  2 ,  Micky D Tortorella  1  3 ,  Linping Wu  1 ,  Shibing Tang  1  4  2
Affiliations
  • 1. Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2. Key Laboratory of Structure-Based Drugs Design& Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Shatin, Hong Kong 999028, China.
  • 4. China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
PMID: 41640090 DOI: 10.1021/acs.jmedchem.5c03503
Abstract

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.

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