|
Type |
Poster Presentation |
Area |
Medicinal Chemistry |
Room No. |
Event Hall |
Time |
4월 19일 (목요일) 11:00~12:30 |
Code |
MEDI.P-625 |
Subject |
First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia |
Authors |
Injae Shin, Hanna Cho, Taebo Sim1,* KU-KIST Graduate School of Converging Science and Technology, Korea University, Korea 1Chemical Kinomics Research Center, Korea Institute of Science and Technology, Korea |
Abstract |
GNF-7, a multi-targeted 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. |
E-mail |
215348@kist.re.kr |
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