2. Academic Validation
  3. 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

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.
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 Liu 4,  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 Liu 4,  Lili Li 5,  Jian Ge 5,  Tao Ren 4,  Shanchun Zhang 6,  Ruixiang Xia 5,  Jing Liu 1 2,  Qingsong Liu 1 2 3 4
Affiliations

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.

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