Abstract |
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.
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Authors | Hanna Cho, Injae Shin, Eunhye Ju, Seunghye Choi, Wooyoung Hur, Haelee Kim, Eunmi Hong, Nam Doo Kim, Hwan Geun Choi, Nathanael S Gray, Taebo Sim |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 61
Issue 18
Pg. 8353-8373
(09 27 2018)
ISSN: 1520-4804 [Electronic] United States |
PMID | 30153003
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Membrane Proteins
- Protein Kinase Inhibitors
- GTP Phosphohydrolases
- NRAS protein, human
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Topics |
- Animals
- Antineoplastic Agents
(chemistry, pharmacology)
- Apoptosis
- Cell Survival
- Female
- GTP Phosphohydrolases
(genetics)
- Humans
- Leukemia, Myeloid, Acute
(drug therapy, genetics, pathology)
- Membrane Proteins
(genetics)
- Mice
- Mice, Nude
- Models, Molecular
- Molecular Structure
- Mutation
- Protein Conformation
- Protein Kinase Inhibitors
(chemistry, pharmacology)
- Signal Transduction
- Structure-Activity Relationship
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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