Discovery of FYJ-195 as a Highly Potent FLT3 Inhibitor against Multiple Acquired Resistance Mutations in Acute Myeloid Leukemia

  • J Med Chem. 2026 Jun 11;69(11):13697-13724. doi: 10.1021/acs.jmedchem.6c00648.
Jin Yang  1 ,  Ling-Yu Zhang  2  3 ,  Xing-Feng Ni  1 ,  Ming-Yu Bai  1 ,  Xu Wang  1 ,  An-Qi Fu  1 ,  Min-Hui Chen  1 ,  Meng-Yuan Zhang  1 ,  Nuo Qiao  1 ,  Zi-Xuan Wang  1 ,  Qing-Qing Li  1 ,  Shu Cai  1 ,  Ying Wang  1 ,  Yu-Sheng Yao  1 ,  Yan-Cheng Yu  1 ,  Wei-Dong Chen  3 ,  Shan-Liang Sun  1 ,  Zhang Zhang  2 ,  Nian-Guang Li  1 ,  Zhi-Hao Shi  4
Affiliations
  • 1. National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China.
  • 2. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 3. Department of Pharmacy, The First Affiliated Hospital of Shantou University Medical college, Shantou, Guangdong 515041, China.
  • 4. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
PMID: 42175928 DOI: 10.1021/acs.jmedchem.6c00648
Abstract

The efficacy of FLT3 inhibitors in acute myeloid leukemia (AML) is severely limited by resistance mutations, particularly the recalcitrant gatekeeper F691L and activation loop D835V/Y variants. Herein, through the structure-guided optimization of our previously reported lead SILA-123, we identified FYJ-195, a highly potent type II FLT3 Inhibitor capable of overcoming these recalcitrant mutants. FYJ-195 exhibited single-digit nanomolar potency against Ba/F3-FLT3-ITD-F691L (IC50 = 9.09 nM) and subnanomolar activity against Ba/F3-FLT3-ITD-D835Y (IC50 = 4.64 nM) and Ba/F3-FLT3-ITD-D835V (IC50 = 0.76 nM). In vivo, FYJ-195 induced profound tumor regression (TGI = 125%) in the MV4-11 xenograft model (10 mg/kg) and achieved robust tumor growth suppression (TGI = 68.6%) in the Ba/F3-FLT3-ITD-F691L model (50 mg/kg), where quizartinib was ineffective. Mechanistic studies confirmed that FYJ-195 effectively blocked FLT3 signaling and induced Apoptosis without observable toxicity. Collectively, FYJ-195 represents a promising lead candidate for drug-resistant AML.

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