2. Academic Validation
  3. Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells

Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells

  • Eur J Med Chem. 2023 Mar 5;249:115140. doi: 10.1016/j.ejmech.2023.115140.
Yulin Liu 1,  Yujiao Wei 1,  Xuan Wang 1,  Lan Ma 1,  Xuechun Li 1,  Yue Sun 1,  Yanjie Wu 1,  Li Zhang 2,  Jiefu Wang 3,  Ming Li 4,  Kun Zhang 5,  Mingming Wei 6,  Guang Yang 7,  Cheng Yang 8
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • 2 Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong, 518000, PR China.
  • 3 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: jwang05@tmu.edu.cn.
  • 4 Cangzhou Institutes for Food and Drug Control, Cangzhou, 061000, PR China. Electronic address: 83991223@qq.com.
  • 5 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: zhangkun1112@163.com.
  • 6 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: mingmingshengwu@163.com.
  • 7 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: guang.yang@nankai.edu.cn.
  • 8 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: 37928480@qq.com.
PMID: 36736154 DOI: 10.1016/j.ejmech.2023.115140
Abstract

Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.

Keywords

Acute myeloid leukemia; Cell differentiation; HDACs/CDKs dual inhibitors; Leukemic stem cells; Molecular hybridization.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149819
    99.60%, HDACs/CDKs Dual Inhibitor