Will newer tyrosine kinase inhibitors have an impact in AML?

Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.
Best practice & research. Clinical haematology (Impact Factor: 2.55). 12/2010; 23(4):489-94. DOI: 10.1016/j.beha.2010.09.008
Source: PubMed

ABSTRACT FLT3 inhibition has been a goal of acute myeloid leukemia (AML) therapy since FLT3 mutations were discovered to have a role in AML. Several FLT3 inhibitors have been developed in the last several years, beginning with less potent, less selective agents. The newer FLT3 inhibitors appear to be more potent in vivo and have shown more promise than the older agents in monotherapy trials.

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    ABSTRACT: Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.
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