Beyer, Mandy and Henninger, Sven J. and Haehnel, Patricia S. and Mustafa, Al-Hassan M. and Gurdal, Ece and Schubert, Bastian and Christmann, Markus and Sellmer, Andreas and Mahboobi, Siavosh and Drube, Sebastian and Sippl, Wolfgang and Kindler, Thomas and Krämer, Oliver H. (2022) Identification of a highly efficient dual type I/II FMS-like tyrosine kinase inhibitor that disrupts the growth of leukemic cells. CELL CHEMICAL BIOLOGY, 29 (3). 398-411.e4. ISSN 2451-9456, 2451-9448
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATIONS; FLT3 INHIBITOR; C-KIT; RESISTANCE MUTATIONS; CLINICAL RESISTANCE; CONFER RESISTANCE; DRUG-RESISTANCE; F691L MUTATION; IN-VITRO |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 05:37 |
| Last Modified: | 30 Jan 2024 05:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58334 |
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