2. Academic Validation
  3. Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia

Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia

  • J Med Chem. 2019 Jan 24;62(2):875-892. doi: 10.1021/acs.jmedchem.8b01594.
Xiaofei Liang 1 2,  Beilei Wang 1 3,  Cheng Chen 1 3,  Aoli Wang 1 2,  Chen Hu 1 3,  Fengming Zou 1 2,  Kailin Yu 1 2,  Qingwang Liu 2 4,  Feng Li 1 3,  Zhenquan Hu 1 2,  Tingting Lu 1 3,  Junjie Wang 1 3,  Li Wang 1 3,  Ellen L Weisberg 5,  Lili Li 6,  Ruixiang Xia 6,  Wenchao Wang 1 2,  Tao Ren 2 4,  Jian Ge 6,  Jing Liu 1 2 4,  Qingsong Liu 1 2 3 4 7
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science , Chinese Academy of Sciences , Hefei , Anhui 230031 , P. R. China.
  • 2 Precision Medicine Research Laboratory of Anhui Province , Hefei , Anhui 230088 , P. R. China.
  • 3 University of Science and Technology of China , Hefei , Anhui 230036 , P. R. China.
  • 4 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science , Chinese Academy of Sciences , Hefei , Anhui 230088 , P. R. China.
  • 5 Department of Medical Oncology, Dana Farber Cancer Institute , Harvard Medical School , 450 Brookline Avenue , Boston , Massachusetts 02115 , United States.
  • 6 Department of Hematology , The First Affiliated Hospital of Anhui Medical University , Hefei , Anhui 230022 , P. R. China.
  • 7 Institute of Physical Science and Information Technology , Anhui University , Hefei , Anhui 230601 , P. R. China.
PMID: 30565931 DOI: 10.1021/acs.jmedchem.8b01594
Abstract

Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI50 values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia Cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of Apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model.

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