2. Academic Validation
  3. Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors

Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors

  • Bioorg Med Chem Lett. 2023 Oct 12:96:129519. doi: 10.1016/j.bmcl.2023.129519.
Xuanmin Lian 1,  Yue Gao 2,  Xuemei Li 1,  Peipei Wang 2,  Lexian Tong 3,  Jia Li 4,  Yubo Zhou 5,  Tao Liu 6
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang 310018, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China. Electronic address: jli@simm.ac.cn.
  • 5 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400, China. Electronic address: ybzhou@mail.shcnc.ac.cn.
  • 6 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: lt601@zju.edu.cn.
PMID: 37838343 DOI: 10.1016/j.bmcl.2023.129519
Abstract

Acute myeloid leukemia (AML) is an aggressive Cancer, which is characterized by clonal expansion of myeloid progenitors in the bone marrow and peripheral blood. FMS-like tyrosine kinase 3 (FLT3) mutations are the most frequently identified mutations, present in approximately 25-30 % AML patients, making FLT3 inhibitors a crucial treatment option for AML. In this study, we described the design, synthesis and biological evaluation of a series of 2-aminopyrimidine derivatives as potent FLT3 inhibitors. Notably, compound 15 displayed potent kinase inhibitory activities against FLT3 (FLT3-WT IC50 = 7.42 ± 1.23 nM; FLT3-D835Y IC50 = 9.21 ± 0.04 nM) and robust antiproliferative activities against MV4-11 cells (IC50 = 0.83 ± 0.15 nM) and MOLM-13 cells (IC50 = 10.55 ± 1.70 nM). Compound 15 also possessed potent antiproliferative activities against BaF3 cells carrying various FLT3-TKD and FLT3-ITD-TKD mutations, indicating its potential to overcome on-target resistance caused by FLT3 mutations. In summary, compound 15 showed promising potential for further exploration as a treatment of AML.

Keywords

2-aminopyrimidine; FLT3 inhibitors; FLT3 mutations; MV4-11.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156410
    FLT3 inhibitor