Abstract
Molecules that control the lineage commitment of hematopoietic stem cells (HSCs) may allow the expansion of enriched progenitor populations for both research and therapeutic uses. In an effort to better understand and control the differentiation of HSCs to megakaryocytes, we carried out an image-based screen of a library of 50,000 heterocycles using primary human CD34(+) cells. A class of naphthyridinone derivatives was identified that induces the differentiation of common myeloid progenitors (CMP) to megakaryocytes. Kinase profiling and subsequent functional assays revealed that these compounds act through inhibition of platelet-derived growth factor receptor (PDGFR) signaling in CMPs. Such molecules may ultimately have clinical utility in the treatment of thrombocytopenia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD34 / metabolism
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Cell Culture Techniques / methods
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cells, Cultured
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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Flow Cytometry / methods
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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High-Throughput Screening Assays / methods*
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Megakaryocytes / cytology*
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Megakaryocytes / metabolism
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Microscopy, Confocal / methods
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Naphthyridines / metabolism
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Naphthyridines / pharmacology*
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Ploidies
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Receptors, Platelet-Derived Growth Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Thrombopoiesis / drug effects*
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Thrombopoiesis / physiology*
Substances
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Antigens, CD34
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Cytokines
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Intercellular Signaling Peptides and Proteins
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Naphthyridines
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Receptors, Platelet-Derived Growth Factor