2. Academic Validation
  3. Identification of the Benzoimidazole Compound as a Selective FLT3 Inhibitor by Cell-Based High-Throughput Screening of a Diversity Library

Identification of the Benzoimidazole Compound as a Selective FLT3 Inhibitor by Cell-Based High-Throughput Screening of a Diversity Library

  • J Med Chem. 2022 Feb 24;65(4):3597-3605. doi: 10.1021/acs.jmedchem.1c02079.
Tian Tian 1 2,  Shengyi Zhang 1 3,  Bingling Luo 1,  Feng Yin 1,  Wenhua Lu 1,  Yiqing Li 4,  Kezhi Huang 4,  Qiao Liu 1,  Peng Huang 1,  G Garcia-Manero 5,  Shijun Wen 1,  Yumin Hu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
  • 2 Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
  • 3 Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 330006, China.
  • 4 Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.
  • 5 Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States.
PMID: 35148084 DOI: 10.1021/acs.jmedchem.1c02079
Abstract

Internal tandem duplication in the FLT3 receptor tyrosine kinase (FLT3/ITD mutation) occurs in approximately 25% of acute myeloid leukemia (AML) patients. To specifically target this driver mutation in AML, we assessed and compared the cell-based cytotoxicity of a diversity library (10,000 compounds) against the normal cell line BaF3 and the isogenic leukemic cell line BaF3/ITD. A benzoimidazole scaffold-based compound (HP1142) was identified as the most selective compound against a series of murine and human leukemia cells with FLT3/ITD. Novel benzoimidazole compounds were further designed to improve the aqueous solubility of HP1142. The most potent compound, HP1328, demonstrated desirable pharmaceutical and pharmacokinetic properties. Treatment with HP1328 significantly reduced the leukemia burden and prolonged the survival of mice with FLT3/ITD leukemia. Our findings establish the specific activity of the benzoimidazole compound against FLT3/ITD leukemia and warrant further investigation in this subset of leukemia patients with poor prognosis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145690
    FLT3/ITD Mutation Inhibitor
  • HY-145691
    FLT3/ITD Mutation Inhibitor