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J Med Chem. 2019 Jan 24;62(2):875-892. doi: 10.1021/acs.jmedchem.8b01594. Epub 2019 Jan 8.

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.

Liang X1,2, Wang B1,3, Chen C1,3, Wang A1,2, Hu C1,3, Zou F1,2, Yu K1,2, Liu Q2,4, Li F1,3, Hu Z1,2, Lu T1,3, Wang J1,3, Wang L1,3, Weisberg EL5, Li L6, Xia R6, Wang W1,2, Ren T2,4, Ge J6, Liu J1,2,4, Liu Q1,2,3,4,7.

Author information

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.

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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