Aminoisoquinoline benzamides, FLT3 and Src-family kinase inhibitors potently inhibit proliferation of acute myeloid leukemia cell lines

作者：Larocque Elizabeth; Naganna N; Ma Xiaochu; Opoku Temeng Clement; Carter Cooper Brandon; Chopra Gaurav; Lapidus Rena G; Sintim Herman O^*

来源：Future Medicinal Chemistry, 2017, 9(11): 1213-1225.

DOI：10.4155/fmc-2017-0067

• acute myeloid leukemia
• FLT3
• MOLM-14
• multikinase inhibitor
• MV4-11
• receptor tyrosine kinase
• SRC-family kinase

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.

• 出版日期2017-7