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First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia.

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.
AuthorsHanna Cho, Injae Shin, Eunhye Ju, Seunghye Choi, Wooyoung Hur, Haelee Kim, Eunmi Hong, Nam Doo Kim, Hwan Geun Choi, Nathanael S Gray, Taebo Sim
JournalJournal of medicinal chemistry (J Med Chem) Vol. 61 Issue 18 Pg. 8353-8373 (09 27 2018) ISSN: 1520-4804 [Electronic] United States
PMID30153003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • GTP Phosphohydrolases
  • NRAS protein, human
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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