TY - JOUR
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
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85053693105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053693105&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b00882
DO - 10.1021/acs.jmedchem.8b00882
M3 - Article
C2 - 30153003
AN - SCOPUS:85053693105
VL - 61
SP - 8353
EP - 8383
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -