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J Med Chem. 2018 Sep 27;61(18):8353-8373. doi: 10.1021/acs.jmedchem.8b00882. Epub 2018 Sep 11.

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

Author information

1
KU-KIST Graduate School of Converging Science and Technology , Korea University , 145 Anam-ro, Seongbuk-gu , Seoul 02841 , Republic of Korea.
2
Chemical Kinomics Research Center , Korea Institute of Science and Technology (KIST) , 5 Hwarangro 14-gil, Seongbuk-gu , Seoul 02792 , Republic of Korea.
3
Daegu-Gyeongbuk Medical Innovation Foundation , 2387 dalgubeol-daero, Suseong-gu , Daegu 42019 , Republic of Korea.
4
NDBio Therapeutics Inc. , 32 Songdogwahak-ro, Yeonsu-gu , Incheon 21984 , Republic of Korea.
5
Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
6
Department of Biological Chemistry & Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.

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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