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
  • 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.

Products