Back to Search Start Over

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

Authors :
Hatcher JM
Weisberg E
Sim T
Stone RM
Liu S
Griffin JD
Gray NS
Source :
ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 Mar 08; Vol. 7 (5), pp. 476-81. Date of Electronic Publication: 2016 Mar 08 (Print Publication: 2016).
Publication Year :
2016

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.

Details

Language :
English
ISSN :
1948-5875
Volume :
7
Issue :
5
Database :
MEDLINE
Journal :
ACS medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
27190596
Full Text :
https://doi.org/10.1021/acsmedchemlett.5b00498