Journal
CELL CHEMICAL BIOLOGY
Volume 29, Issue 3, Pages 398-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2021.10.011
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Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [KR 2291/8-1, 393547839]
- Brigitte und Dr. Konstanze Wegener-Stiftung
- University Medical Center Mainz
- DFG [KR2291-9-1/12-1/14-1]
- Wilhelm Sander Foundation [2019.086.1]
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This study shows that the tyrosine kinase inhibitor marbotinib effectively suppresses the phosphorylation of FLT3-ITD and the growth of AML cells, including those with FLT3 inhibitors resistant mutations. Marbotinib has high selectivity for FLT3 and can alter signaling, similar to genetic elimination of FLT3-ITD. In addition, the water-soluble marbotinib-carbamate can significantly prolong the survival of mice with FLT3-driven leukemia.
Internal tandem duplications (ITDs) in the FMS-like tyrosine kinase-3 (FLT3) are causally linked to acute myeloid leukemia (AML) with poor prognosis. Available FLT3 inhibitors (FLT3i) preferentially target inactive or active conformations of FLT3. Moreover, they co-target kinases for normal hematopoiesis, are vulnerable to therapy-associated tyrosine kinase domain (TKD) FLT3 mutants, or lack low nanomolar activity. We show that the tyrosine kinase inhibitor marbotinib suppresses the phosphorylation of FLT3-ITD and the growth of permanent and primary AML cells with FLT3-ITD. This also applies to leukemic cells carrying FLT3-ITD/TKD mutants that confer resistance to clinically used FLT3i. Marbotinib shows high selectivity for FLT3 and alters signaling, reminiscent of genetic elimination of FLT3-ITD. Molecular docking shows that marbotinib fits in opposite orientations into inactive and active conformations of FLT3. The water-soluble marbotinib-carbamate significantly prolongs survival of mice with FLT3-driven leukemia. Marbotinib is a nanomolar next -generation FLT3i that represents a hybrid inhibitory principle.
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