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

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

doi:10.4155/fmc-2017-0067

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

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

Authors

Elizabeth Larocque¹, N Naganna¹, Xiaochu Ma^{1

2}, Clement Opoku-Temeng^{1

2}, Brandon Carter-Cooper³, Gaurav Chopra^{1

4

5}, Rena G Lapidus³, Herman O Sintim^{1

4

5}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Apoptosis
Benzamides / chemical synthesis*
Benzamides / pharmacology
Binding Sites
Cell Line, Tumor
Cell Proliferation
Cell Survival
Humans
Isoquinolines / chemical synthesis*
Isoquinolines / pharmacology
Leukemia, Myeloid, Acute / drug therapy*
Molecular Docking Simulation
Mutation
Protein Binding
Protein Conformation
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
src-Family Kinases / antagonists & inhibitors*

Substances

Antineoplastic Agents
Benzamides
Isoquinolines
FLT3 protein, human
fms-Like Tyrosine Kinase 3
src-Family Kinases

Grants and funding

P30 CA023168/CA/NCI NIH HHS/United States