氨基异喹啉苯甲酰胺类，即FLT3和Src家族激酶抑制剂，可有效抑制急性髓系白血病细胞系的增殖。
Aminoisoquinoline benzamides, FLT3 and Src-family kinase inhibitors, potently inhibit proliferation of acute myeloid leukemia cell lines.
作者信息
Larocque Elizabeth, Naganna N, Ma Xiaochu, Opoku-Temeng Clement, Carter-Cooper Brandon, Chopra Gaurav, Lapidus Rena G, Sintim Herman O
机构信息
Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
On the Chemistry & Biochemistry Graduate Program, University of Maryland, College Park, MD 20742, USA.
出版信息
Future Med Chem. 2017 Jul;9(11):1213-1225. doi: 10.4155/fmc-2017-0067. Epub 2017 May 11.
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.
目的
突变或过表达的FLT3驱动约30%的已报道急性髓系白血病（AML）。目前，FLT3抑制剂已显示出持久的临床反应，但由于突变驱动的耐药机制，使用FLT3抑制剂使AML完全缓解仍难以实现。开发同时靶向其他下游致癌激酶的FLT3抑制剂可能对抗耐药机制。
结果
4-取代氨基异喹啉苯甲酰胺可有效抑制Src家族激酶和FLT3，包括继发性突变，如FLT3 D835。将氨基异喹啉苯甲酰胺修饰为氨基喹啉或氨基喹唑啉可消除FLT3和Src家族激酶的结合。
结论
先导氨基异喹啉可有效抑制FLT3驱动的AML细胞系MV4-11和MOLM-14。这些氨基异喹啉苯甲酰胺代表了具有高潜力转化为抗癌药物的新型激酶支架。
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