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J Med Chem. 2017 Oct 26;60(20):8407-8424. doi: 10.1021/acs.jmedchem.7b00840. Epub 2017 Oct 17.

Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML.

Wang A1,2, Li X1,2, Chen C1,3, Wu H1,2, Qi Z1,2, Hu C1,3, Yu K1,3, Wu J1,3, Liu J4, Liu X1,2, Hu Z1,2, Wang W1,2, Wang W1,3, Wang W1,2, Wang L1,3, Wang B1,3, Liu Q4, Li L5, Ge J5, Ren T4, Zhang S6, Xia R5, Liu J1,2, Liu Q1,2,3,4.

Author information

1
High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
2
CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, 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 Hematology, The First Affiliated Hospital of Anhui Medical University , Hefei, Anhui 230022, P. R. China.
6
Hefei Cosource Medicine Technology Co. Ltd. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.

Abstract

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3-ITD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavailability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg-1 day-1, TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-ITD positive AML.

PMID:
28956923
DOI:
10.1021/acs.jmedchem.7b00840
[Indexed for MEDLINE]

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