2. Academic Validation
  3. Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1

Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1

  • RSC Med Chem. 2023 Dec 7;15(2):539-552. doi: 10.1039/d3md00597f.
Minjie Deng 1,  Yue Gao 2 3,  Peipei Wang 2 3,  Wenjing Du 1,  Gaoya Xu 2 3,  Jia Li 2 3 4 5,  Yubo Zhou 3 5,  Tao Liu 1 6 7
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University Zijingang Campus Hangzhou 310058 P.R. China [email protected].
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine Nanjing 210023 P.R. China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 P.R. China [email protected].
  • 4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery Yantai 264117 P.R. China.
  • 5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Zhongshan 528400 P.R. China.
  • 6 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, Zhejiang University Hangzhou 310058 P.R. China.
  • 7 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University Hangzhou 310058 P.R. China.
PMID: 38389894 DOI: 10.1039/d3md00597f
Abstract

Here, we discover an FLT3/Chk1 dual inhibitor (30) that exhibits excellent kinase potency and antiproliferative activity against MV4-11 cells. Simultaneously, 30 possesses high selectivity over c-Kit Enzyme and low hERG inhibitory ability. Compound 30, meanwhile, overcomes varied resistance in BaF3 cell lines carrying FLT3-TKD and FLT3-ITD mutations. Moreover, 30 demonstrates favorable oral PK properties and kinase selectivity. These conclusions support that compound 30 may be a promising potential FLT3/Chk1 dual agent for further development.

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