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Wu-5, a novel USP10 inhibitor, enhances crenolanib-induced FLT3-ITD-positive AML cell death via inhibiting FLT3 and AMPK pathways.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2021 Apr; Vol. 42 (4), pp. 604-612. Date of Electronic Publication: 2020 Jul 21. - Publication Year :
- 2021
-
Abstract
- The kinase FLT3 internal tandem duplication (FLT3-ITD) is related to poor clinical outcomes of acute myeloid leukemia (AML). FLT3 inhibitors have provided novel strategies for the treatment of FLT3-ITD-positive AML. But they are limited by rapid development of acquired resistance and refractory in monotherapy. Recent evidence shows that inducing the degradation of FLT3-mutated protein is an attractive strategy for the treatment of FLT3-ITD-positive AML, especially those with FLT3 inhibitor resistance. In this study we identified Wu-5 as a novel USP10 inhibitor inducing the degradation of FLT3-mutated protein. We showed that Wu-5 selectively inhibited the viability of FLT3 inhibitor-sensitive (MV4-11, Molm13) and -resistant (MV4-11R) FLT3-ITD-positive AML cells with IC <subscript>50</subscript> of 3.794, 5.056, and 8.386 μM, respectively. Wu-5 (1-10 μM) dose-dependently induced apoptosis of MV4-11, Molm13, and MV4-11R cells through the proteasome-mediated degradation of FLT3-ITD. We further demonstrated that Wu-5 directly interacted with and inactivated USP10, the deubiquitinase for FLT3-ITD in vitro (IC <subscript>50</subscript> value = 8.3 µM) and in FLT3-ITD-positive AML cells. Overexpression of USP10 abrogated Wu-5-induced FLT3-ITD degradation and cell death. Also, the combined treatment of Wu-5 and crenolanib produced synergistic cell death in FLT3-ITD-positive cells via the reduction of both FLT3 and AMPKα proteins. In support of this, AMPKα inhibitor compound C synergistically enhanced the anti-leukemia effect of crenolanib, while AMPKα activator metformin inhibited the anti-leukemia effect of crenolanib. In summary, we demonstrate that Wu-5, a novel USP10 inhibitor, can overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKα pathway.
- Subjects :
- AMP-Activated Protein Kinases metabolism
Antineoplastic Agents pharmacology
Benzimidazoles pharmacology
Cell Line, Tumor
Drug Synergism
Humans
Leukemia, Myeloid, Acute drug therapy
Piperidines pharmacology
Proteasome Endopeptidase Complex metabolism
Proteolysis drug effects
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
fms-Like Tyrosine Kinase 3 metabolism
Apoptosis drug effects
Drug Resistance, Neoplasm drug effects
Enzyme Inhibitors pharmacology
Signal Transduction drug effects
Thiophenes pharmacology
Ubiquitin Thiolesterase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 42
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 32694757
- Full Text :
- https://doi.org/10.1038/s41401-020-0455-x