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Future Med Chem. 2017 Jul;9(11):1213-1225. doi: 10.4155/fmc-2017-0067. Epub 2017 May 11.

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

Author information

1
Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
2
On the Chemistry & Biochemistry Graduate Program, University of Maryland, College Park, MD 20742, USA.
3
Translational Core Laboratory, University of Maryland Greenebaum Cancer Center, 655 W Baltimore Street, Baltimore, MD 21201, USA.
4
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
5
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.

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.

KEYWORDS:

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

PMID:
28490193
PMCID:
PMC5941727
DOI:
10.4155/fmc-2017-0067
[Indexed for MEDLINE]
Free PMC Article

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