Elizabeth Larocque1, N Naganna1, Xiaochu Ma1,2, Clement Opoku-Temeng1,2, Brandon Carter-Cooper3, Gaurav Chopra1,4,5, Rena G Lapidus3, Herman O Sintim1,4,5. 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.
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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