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Updated: Mar 31, 2026
Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors
Published on: October 17, 2025
New selective and allosteric FLT3 inhibitors show efficacy against resistant acute myeloid leukemia cells
Shuai-Shuai Ge1,2, Qiao-Cheng Qiu1,2, Jingsheng Hua3
1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
Activating FLT3 mutations confer a poor prognosis in acute myeloid leukemia (AML). FLT3 inhibitors significantly improved the clinical outcomes of FLT3-mutated AML. However, all clinically approved inhibitors target the ATP-binding pocket of FLT3. The acquired FLT3 mutations in the ATP-binding pocket, including mutations at D835 and F691, are common mechanisms of leukemia relapse. Using druggable site prediction (DSP) and high-throughput virtual screening, we revealed that the predicted site 1 region was promising for allosteric inhibitor development, and F-17 was identified as the first potential allosteric FLT3 inhibitor. F-17 exhibited high affinity for site 1 in an ATP non-competitive manner. KINOMEscan analysis showed that F-17 was significantly selective toward FLT3 over other homologous kinases of the RTK family. Moreover, F-17 showed potent selectivity and inhibition activity for FLT3-mutated cells both in vitro and in vivo. Collectively, the work provided a new insight for FLT3 inhibitor development.
Insights
A new allosteric FLT3 inhibitor, F-17, shows promise for treating acute myeloid leukemia (AML) by targeting a different site than current drugs, potentially overcoming resistance mechanisms.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Activating FLT3 mutations are linked to poor prognosis in acute myeloid leukemia (AML).
- Current FLT3 inhibitors target the ATP-binding pocket, but resistance mutations (e.g., D835, F691) cause relapse.
Purpose of the Study:
- To identify novel allosteric FLT3 inhibitors targeting a different site to overcome resistance.
- To characterize the first potential allosteric FLT3 inhibitor, F-17.
Main Methods:
- Druggable site prediction (DSP) and high-throughput virtual screening identified potential allosteric sites.
- Biochemical assays (e.g., KINOMEscan) assessed F-17's affinity, selectivity, and inhibition of FLT3.
- In vitro and in vivo studies evaluated F-17's efficacy in FLT3-mutated AML cells.
Main Results:
- Site 1 was identified as a promising allosteric target for FLT3 inhibitor development.
- F-17 was identified as the first potential allosteric FLT3 inhibitor, binding to site 1 non-competitively.
- F-17 demonstrated high selectivity for FLT3 over other kinases and potent inhibition of FLT3-mutated AML cells.
Conclusions:
- Allosteric inhibition of FLT3 represents a novel therapeutic strategy for AML.
- F-17 is a potent and selective allosteric FLT3 inhibitor with potential for clinical development.
- This study provides new insights into targeting FLT3 mutations in AML to overcome drug resistance.
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