- First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia
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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.
- 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
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p. 8353 - 8383
(2018/09/27)
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- A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl
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The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydr
- Choi, Hwan Geun,Ren, Pingda,Adrian, Francisco,Sun, Fangxian,Lee, Hyun Soo,Wang, Xia,Ding, Qiang,Zhang, Guobao,Xie, Yongping,Zhang, Jianming,Liu, Yi,Tuntland, Tove,Warmuth, Markus,Manley, Paul W.,Mestan, Jürgen,Gray, Nathanael S.,Sim, Taebo
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experimental part
p. 5439 - 5448
(2010/11/05)
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