Discovery of highly potent mTOR inhibitors aimed at suppressing the progression of acute myeloid leukemia

  • Bioorg Chem. 2025 Apr:157:108287. doi: 10.1016/j.bioorg.2025.108287.
Yuanyuan Li  1 ,  Qiu Han  1 ,  Qiwen Sun  1 ,  Xue Wang  2 ,  Yunsheng Ran  1 ,  Yifei Ma  3 ,  Jiangrong Lu  1 ,  Ziqi Jin  2 ,  Jing Huang  1 ,  Yujie Wang  1 ,  Jianta Wang  1 ,  Yue'e Chai  4 ,  Hongliang Li  5 ,  Ji-Quan Zhang  6
Affiliations
  • 1. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 561113, P.R. China.
  • 2. School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, PR China.
  • 3. The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China.
  • 4. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 561113, P.R. China. Electronic address: [email protected].
  • 5. School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, PR China. Electronic address: [email protected].
  • 6. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 561113, P.R. China. Electronic address: [email protected].
PMID: 40010131 DOI: 10.1016/j.bioorg.2025.108287
Abstract

Acute myeloid leukemia (AML) is a common hematological malignancy with complex etiology; however, current standard chemotherapy regimens for AML show limited efficacy and unsatisfactory tolerability. Herein, a novel class of trisubstituted triazine mTOR inhibitors was designed and synthesized, and the optimal compound, HPT-11, exhibited potent inhibition against mTOR kinase and Molm-13 cell proliferation activities with inhibitory IC50 values of 0.7 and 12 nM, respectively. An antitumor mechanism investigation demonstrated that HPT-11 could potently block the downstream signaling pathway of mTOR and effectively induce Apoptosis and Autophagy. In addition, in vitro metabolic stability tests further confirmed the stable profiles of HPT-11 in artificial gastrointestinal fluids, rat plasma, and liver microsomes incubating conditions. Overall, our current medicinal chemistry work confirmed that compound HPT-11 is a potent mTOR Inhibitor with promising activity in vitro, suggesting its potential as a candidate for further development in the treatment of AML.

Keywords
Acute myeloid leukemia; Antitumor activity; Kinase; Synthesis; mTOR inhibitor.
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