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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)8353-8383
Number of pages31
JournalJournal of Medicinal Chemistry
Volume61
Issue number18
DOIs
Publication statusPublished - 2018 Sep 27

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Acute Myeloid Leukemia
Phosphotransferases
Heterografts
Pharmacokinetics
Apoptosis
Mutation
Growth
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Cho, Hanna ; Shin, Injae ; Ju, Eunhye ; Choi, Seunghye ; Hur, Wooyoung ; Kim, Haelee ; Hong, Eunmi ; Kim, Nam Doo ; Choi, Hwan Geun ; Gray, Nathanael S. ; Sim, Taebo. / First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 18. pp. 8353-8383.
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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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Cho, H, Shin, I, Ju, E, Choi, S, Hur, W, Kim, H, Hong, E, Kim, ND, Choi, HG, Gray, NS & Sim, T 2018, 'First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia', Journal of Medicinal Chemistry, vol. 61, no. 18, pp. 8353-8383. https://doi.org/10.1021/acs.jmedchem.8b00882

First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia. / Cho, Hanna; Shin, Injae; Ju, Eunhye; Choi, Seunghye; Hur, Wooyoung; Kim, Haelee; Hong, Eunmi; Kim, Nam Doo; Choi, Hwan Geun; Gray, Nathanael S.; Sim, Taebo.

In: Journal of Medicinal Chemistry, Vol. 61, No. 18, 27.09.2018, p. 8353-8383.

Research output: Contribution to journalArticle

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T1 - First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

AU - Cho, Hanna

AU - Shin, Injae

AU - Ju, Eunhye

AU - Choi, Seunghye

AU - Hur, Wooyoung

AU - Kim, Haelee

AU - Hong, Eunmi

AU - Kim, Nam Doo

AU - Choi, Hwan Geun

AU - Gray, Nathanael S.

AU - Sim, Taebo

PY - 2018/9/27

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N2 - 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.

AB - 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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