sc1-compound has been researched along with Leukemia--Myeloid--Acute* in 1 studies
1 other study(ies) available for sc1-compound and Leukemia--Myeloid--Acute
Article | Year |
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First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia.
GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound 11i is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML. Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Survival; Female; GTP Phosphohydrolases; Humans; Leukemia, Myeloid, Acute; Membrane Proteins; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Mutation; Protein Conformation; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship; Tumor Cells, Cultured; Xenograft Model Antitumor Assays | 2018 |