2. Academic Validation
  3. Discovery of highly potent mTOR inhibitors aimed at suppressing the progression of acute myeloid leukemia

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

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: 2253378094@qq.com.
  • 5 School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, PR China. Electronic address: lihongliang@ynu.edu.cn.
  • 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: zjqgmc@163.com.
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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