2. Academic Validation
  3. Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia

Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia

  • Eur J Med Chem. 2023 Oct 5;258:115543. doi: 10.1016/j.ejmech.2023.115543.
Chengbin Yang 1,  Yi Chen 2,  Tianze Wu 2,  Yunjian Gao 2,  Xiaofeng Liu 2,  Yongtai Yang 2,  Yun Ling 2,  Yu Jia 2,  Mingli Deng 3,  Jianxin Wang 4,  Yaming Zhou 5
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China; Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, China.
  • 2 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China.
  • 3 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China. Electronic address: mldeng@fudan.edu.cn.
  • 4 Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, China.
  • 5 Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, 200433, China. Electronic address: ymzhou@fudan.edu.cn.
PMID: 37329712 DOI: 10.1016/j.ejmech.2023.115543
Abstract

PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC50 values against PI3Kα/β/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC50 values of 0.092 μM and 0.084 μM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.

Keywords

7-Azaindzaole; Acute myeloid leukemia; Hematological malignancies; PI3K-AKT-mTOR pathway; PI3K/mTOR dual inhibitor; Phosphatidylinositol 3-kinase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155066
    98.40%, PI3K/mTOR Inhibitor