2. Academic Validation
  3. Discovery of novel sitolactone derivative leading to PANoptosis and differentiation of acute myeloid leukemia cells

Discovery of novel sitolactone derivative leading to PANoptosis and differentiation of acute myeloid leukemia cells

  • Eur J Med Chem. 2025 Apr 15:288:117360. doi: 10.1016/j.ejmech.2025.117360.
Jiefu Wang 1,  Ning Wang 2,  Mengmeng Wang 3,  Ning Liu 3,  Chenyang Wang 3,  Ning Li 3,  Linrong Mu 3,  Yurui Jiang 3,  Jia Chen 3,  Jinxiao Li 3,  Guang Yang 4,  Junfeng Wang 5,  Shuangwei Liu 6,  Kun Zhang 7
Affiliations

Affiliations

  • 1 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China.
  • 2 Center for Drug Evaluation, Shaanxi Medical Products Administration, Xi'an, Shaanxi, 710065, PR China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
  • 3 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
  • 4 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: Guang.yang@nankai.edu.cn.
  • 5 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China. Electronic address: wangjunfeng@tjmuch.com.
  • 6 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: shuangwei.liu@nankai.edu.cn.
  • 7 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: zhangkun1112@163.com.
PMID: 39983554 DOI: 10.1016/j.ejmech.2025.117360
Abstract

Acute Myeloid Leukemia (AML) is a devastating hematologic malignancy. Chemotherapy remains the primary treatment, offering rapid disease control and potential complete remission. However, more than half of the patients develop resistance and relapse, significantly reducing patient survival. Research has shown that drug-resistance and recurrence of AML are closely linked to leukemic stemness. Consequently, discovering new anti-Leukemia stem cell (LSC) compounds is a promising strategy for the treatment of AML in clinic. Additionally, the recent focus on inducing non-apoptotic programmed cell death in AML cells presents an alternative direction for therapeutic drug development, targeting current anti-apoptotic pathways. In this study, novel Sitolactone analogues, potential anti-LSCs compounds, were designed and synthesized based on the "biomimetic design" strategy. Compound 42 was found to significantly inhibit proliferation of AML cells. Subsequent biological evaluation revealed that this compound not only reduced the population of LSCs but also effectively induced PANoptosis in AML cells. Given the active compound's poor water solubility, a prodrug modification strategy was employed to enhance in vivo delivery with superior oral bioavailability and PK properties. This approach significantly suppressed AML cell growth in a mouse orthotropic model with favorable in vivo tolerance.

Keywords

Acute myeloid leukemia; Leukemia stem cell; PANoptosis; Prodrug; Sitolactone.

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