First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia
- Authors
- 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
- Issue Date
- 27-9월-2018
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, v.61, no.18, pp.8353 - 8373
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- Volume
- 61
- Number
- 18
- Start Page
- 8353
- End Page
- 8373
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/73053
- DOI
- 10.1021/acs.jmedchem.8b00882
- ISSN
- 0022-2623
- 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 lli 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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Collections - Graduate School > KU-KIST Graduate School of Converging Science and Technology > 1. Journal Articles
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