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

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

Future Med Chem. 2017 May 11;:

Authors: Larocque E, Naganna N, Ma X, Opoku-Temeng C, Carter-Cooper B, Chopra G, Lapidus RG, Sintim HO

Abstract
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.

PMID: 28490193 [PubMed - as supplied by publisher]

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