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

doi:10.1021/acs.jmedchem.8b00882

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

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

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 language	English
Pages (from-to)	8353-8383
Number of pages	31
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00882
Publication status	Published - 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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10.1021/acs.jmedchem.8b00882

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@article{80e6ce1d86dc447fa62d58ef4360440c,

title = "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.",

author = "Hanna Cho and Injae Shin and Eunhye Ju and Seunghye Choi and Wooyoung Hur and Haelee Kim and Eunmi Hong and Kim, {Nam Doo} and Choi, {Hwan Geun} and Gray, {Nathanael S.} and Taebo Sim",

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: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = sep,

day = "27",

doi = "10.1021/acs.jmedchem.8b00882",

language = "English",

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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

N1 - 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.

PY - 2018/9/27

Y1 - 2018/9/27

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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First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

Abstract

Bibliographical note

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