期刊
FUTURE MEDICINAL CHEMISTRY
卷 9, 期 11, 页码 1213-1225出版社
FUTURE SCI LTD
DOI: 10.4155/fmc-2017-0067
关键词
acute myeloid leukemia; FLT3; MOLM-14; multikinase inhibitor; MV4-11; receptor tyrosine kinase; SRC-family kinase
资金
- Purdue University
- NIH [P30 CA023168]
- China Scholarship Council [201406140119]
Aim: Mutated or overexpressed FLT3 drives about 30% of reported acute myeloid leukemia (AML). Currently, FLT3 inhibitors have shown durable clinical responses but a complete remission of AML with FLT3 inhibitors remains elusive due to mutation-driven resistance mechanisms. The development of FLT3 inhibitors that also target other downstream oncogenic kinases may combat the resistance mechanism. Results: 4-substituted aminoisoquinoline benzamides potently inhibit Src-family kinases and FLT3, including secondary mutations, such as FLT3D835. Modifications of aminoisoquinoline benzamide to aminoquinoline or aminoquinazoline abrogated FLT3 and Src-family kinase binding. Conclusion: The lead aminoisoquinolines potently inhibited FLT3-driven AML cell lines, MV4-11 and MOLM-14. These aminoisoquinoline benzamides represent new kinase scaffolds with high potential to be translated into anticancer agents.
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