Abstract
Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3. Because the relevant DUBs for FLT3 are not known, we assembled a focused library of most reported small-molecule DUB inhibitors and carried out a cellular phenotypic screen to identify compounds that could induce the degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3. Targeting of USP10 showed efficacy in preclinical models of mutant-FLT3 AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven leukemia.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Female
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, Inbred NOD
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Molecular Structure
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Mutation
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Thiophenes / chemistry
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Thiophenes / pharmacology*
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Tumor Cells, Cultured
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Ubiquitin / metabolism
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Ubiquitin Thiolesterase / antagonists & inhibitors*
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / metabolism
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism*
Substances
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1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Small Molecule Libraries
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Thiophenes
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USP10 protein, human
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Ubiquitin
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FLT3 protein, human
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fms-Like Tyrosine Kinase 3
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Ubiquitin Thiolesterase
Associated data
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PubChem-Substance/341138788
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PubChem-Substance/341138789