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Dual SYK-HDAC Inhibitor Elicits Striking Efficacy against Acute Myeloid Leukemia: Rational Design; Synthesis; and Biological Evaluation
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DOI：10.1021/acs.jmedchem.6c00039.png)
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Abstract
En 中文
An integrated transcriptomic and survival analysis led to the identification of SYK and HDAC isoforms as age- and FLT3-dependent prognostic markers in acute myeloid leukemia (AML). Driven by the aforementioned, our research group employed a classical ligand-based hybrid pharmacophore strategy to furnish dual-target hybrid frameworks. Antitumor profiling culminated in a tractable bifunctional agent (Compound 14, dual SYK-HDAC inhibitor) endowed with substantial cell growth inhibitory effects against MV4–11 cell lines (AML cell lines harboring FLT3-ITD mutations). Compound 14 downregulated the expression levels of p-SYK and modulated the expression levels of the biomarkers associated with intracellular HDAC inhibition. Transcriptomic profiling revealed significantly suppressed lipid-associated metabolic pathways with Compound 14 treatment. Moreover, Compound 14 demonstrated an impressive pharmacokinetic profile and exerted significant antitumor efficacy in the FLT3-ITD-positive AML xenograft mouse model (approximately 80% decrease in tumor mass). Also, biochemical blood analysis and histopathological studies revealed that Compound 14 demonstrated a good safety profile.
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