First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

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

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17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)8353-8383
Number of pages31
JournalJournal of Medicinal Chemistry
Issue number18
Publication statusPublished - 2018 Sept 27

Bibliographical note

Funding Information:
This work was supported by Korea Institute of Science and Technology (KIST), the KU-KIST Graduate School of Converging Science and Technology Program, a grant (D33400) from the Korea Basic Science Institute, Support for Candidate Development Program (NRF-2016M3A9B5940991) and Pioneer Research Center Program (NRF-2014M3C1A3051476) of the National Research Foundation of Korea funded by the Ministry of Science and ICT.

Publisher Copyright:
© 2018 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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