Aminoisoquinoline benzamides, FLT3 and Src-family kinase inhibitors, potently inhibit proliferation of acute myeloid leukemia cell lines. (July 2017)

• Record Type: Journal Article
• Authors: Larocque, Elizabeth; Naganna, N; Ma, Xiaochu; Opoku-Temeng, Clement; Carter-Cooper, Brandon; Chopra, Gaurav; Lapidus, Rena G; Sintim, Herman O
• Is Part Of: Future medicinal chemistry. Volume 9:Number 11(2017)
• Page Start: 1213
• Page End: 1225
• Publication Date: 2017-07
• Subjects: acute myeloid leukemia -- FLT3 -- MOLM-14 -- multikinase inhibitor -- MV4–11 -- receptor tyrosine kinase -- SRC-family kinase; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2017-0067
• Languages: English
• ISSNs: 1756-8919

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.