Discovery of FYJ-195 as a Highly Potent FLT3 Inhibitor against Multiple Acquired Resistance Mutations in Acute Myeloid Leukemia
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Published on: October 17, 2025
Jin Yang1, Ling-Yu Zhang2,3, Xing-Feng Ni1
1National 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.
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.
Insights
A new FLT3 inhibitor, FYJ-195, effectively targets drug-resistant acute myeloid leukemia (AML) mutations. This potent compound overcomes resistance and shows significant efficacy in preclinical models, offering a promising therapeutic option.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) treatment efficacy is hampered by FLT3 resistance mutations.
- Gatekeeper (F691L) and activation loop (D835V/Y) mutations limit current FLT3 inhibitor effectiveness.
Purpose of the Study:
- To develop a novel type II FLT3 inhibitor overcoming resistance mutations.
- To characterize the preclinical efficacy and safety of FYJ-195.
Main Methods:
- Structure-guided optimization of lead compound SILA-123.
- In vitro enzymatic assays and cell-based potency testing.
- In vivo xenograft studies in AML models and toxicity assessments.
Main Results:
- FYJ-195 demonstrated potent inhibition against FLT3 resistance mutants (nM to sub-nM IC50 values).
- Significant tumor regression in MV4-11 xenografts and tumor growth suppression in a resistant Ba/F3-FLT3-ITD-F691L model.
- FYJ-195 effectively inhibited FLT3 signaling, induced apoptosis, and showed no observable toxicity.
Conclusions:
- FYJ-195 is a potent type II FLT3 inhibitor effective against key resistance mutations.
- FYJ-195 exhibits promising preclinical efficacy and safety for drug-resistant AML.
- FYJ-195 represents a potential therapeutic candidate for overcoming FLT3 inhibitor resistance in AML.
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