Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor

Title
Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor
Authors
심태보John M. HatcherEllen WeisbergRichard M. StoneSuiyang LiuJames D. GriffinNathanael S. Gray
Issue Date
2016-05
Publisher
ACS MEDICINAL CHEMISTRY LETTERS
Citation
VOL 7, NO 5-481
Abstract
For a subpopulation of acute myeloid leukemia (AML) patients, the mutationally activated tyrosine kinase FLT3, has emerged as a promising target for therapy. The development of drug resistance due to mutation is a growing concern for mutant FLT3 inhibitors, such as PKC412, Quizartinib, PLX3397, and Crenolanib. Thus, there is a need to develop novel FLT3 inhibitors that overcome these mutations. Here we report the development of a novel type I ATP competitive inhibitor, JH-IX-179, that is extremely potent and selective for FLT3. JH-IX-179 also has the highest affinity for three constitutively active isoforms of FLT3 (FLT3-ITD, FLT3-N841I, and FLT3-D835V) compared to a panel 456 other kinases. The unique and specific kinase inhibition profile suggests that this chemotype may represent an attractive starting point for the development of further improved FLT3 inhibitors with therapeutic potential in tumors harboring deregulated FLT3 activity.
URI
http://pubs.kist.re.kr/handle/201004/65040
ISSN
1948-5875
Appears in Collections:
KIST Publication > Article
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