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

Aoli Wang; Xixiang Li; Cheng Chen; Hong Wu; Ziping Qi; Chen Hu; Kailin Yu; Jiaxin Wu; Juan Liu; Xiaochuan Liu; Zhenquan Hu; Wei Wang; Wenliang Wang; Wenchao Wang; Li Wang; Beilei Wang; Qingwang Liu; Lili Li; Jian Ge; Tao Ren; Shanchun Zhang; Ruixiang Xia; Jing Liu; Qingsong Liu

doi:10.1021/acs.jmedchem.7b00840

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

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

Authors

Aoli Wang^{1

2}, Xixiang Li^{1

2}, Cheng Chen^{1

3}, Hong Wu^{1

2}, Ziping Qi^{1

2}, Chen Hu^{1

3}, Kailin Yu^{1

3}, Jiaxin Wu^{1

3}, Juan Liu⁴, Xiaochuan Liu^{1

2}, Zhenquan Hu^{1

2}, Wei Wang^{1

2}, Wenliang Wang^{1

3}, Wenchao Wang^{1

2}, Li Wang^{1

3}, Beilei Wang^{1

3}, Qingwang Liu⁴, Lili Li⁵, Jian Ge⁵, Tao Ren⁴, Shanchun Zhang⁶, Ruixiang Xia⁵, Jing Liu^{1

2}, Qingsong Liu^{1

2

3

4}

Affiliations

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.

PMID: 28956923
DOI: 10.1021/acs.jmedchem.7b00840

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Discovery*
Humans
In Situ Nick-End Labeling
Mice
Mice, Nude
Phenylurea Compounds / chemistry
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proton Magnetic Resonance Spectroscopy
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Spectrometry, Mass, Electrospray Ionization
Xenograft Model Antitumor Assays
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

CHMFL-FLT3-213 compound
Phenylurea Compounds
Protein Kinase Inhibitors
Pyrazoles
FLT3 protein, human
fms-Like Tyrosine Kinase 3