2. Academic Validation
  3. Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia

Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia

  • Drug Dev Res. 2024 Dec;85(8):e70022. doi: 10.1002/ddr.70022.
Jin Yang 1,  Yan Zhang 1,  Yue-Chu Li 1,  Qing-Xin Wang 1,  Meng-Yuan Zhang 1,  Yu-Jing Xu 1,  Jing-Jing Wang 1,  Xiao-Ting Liang 1,  Xiao-Long Jing 1,  Shuang-Shuang Zhou 1,  Qing-Qing Li 1,  Zi-Xuan Wang 1,  Yun Zhou 1,  Nuo Qiao 1,  Tian-Hua Wei 1,  Ning Ding 1,  Xin Xue 1,  Yan-Cheng Yu 1,  Xiao-Long Wang 1,  Shan-Liang Sun 1,  Wei-Chen Dai 1,  Nian-Guang Li 1,  Zhi-Hao Shi 2
Affiliations

Affiliations

  • 1 National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 2 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, Jiangsu, China.
PMID: 39569546 DOI: 10.1002/ddr.70022
Abstract

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure-activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC50 = 2.68 μM) and MOLM-13 (IC50 = 1.03 μM). In our cellular mechanistic studies, FW-1 also effectively induced Apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 Inhibitor, warranting further optimization.

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