2. Academic Validation
  3. Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

  • J Med Chem. 2021 Oct 14;64(19):14664-14701. doi: 10.1021/acs.jmedchem.1c01196.
Zhijie Wang 1,  Jiongheng Cai 1,  Jiwei Ren 1,  Yun Chen 2,  Yingli Wu 3,  Jie Cheng 1,  Kun Jia 1,  Fei Huang 1,  Zitian Cheng 1,  Tiancheng Sheng 4,  Shiyu Song 5,  Hao Heng 6,  Yifan Zhu 7,  Weifang Tang 1,  Hongmei Li 1,  Tao Lu 8,  Yadong Chen 9,  Shuai Lu 1
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 2 Edmond H. Fischer Translational Medical Research Laboratory, Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, P. R. China.
  • 3 Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P. R. China.
  • 4 School of Engineering, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 5 School of Life Sciences and Technology, China Pharmaceutical University, Nanjing 210038, P. R. China.
  • 6 Department of Polymer Science & Engineering, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China.
  • 7 School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P.R. China.
  • 8 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
  • 9 Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing 211198, P. R. China.
PMID: 34550682 DOI: 10.1021/acs.jmedchem.1c01196
Abstract

Secondary mutations of FLT3 have become the main mechanism of FLT3 Inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure-activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and Apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139619
    FLT3 Inhibitor