Linked Life Data

19183186

Source:http://linkedlifedata.com/resource/pubmed/id/19183186

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2009-3-5
pubmed:abstractText
Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H-indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of both compounds with chemotherapy revealed synergistic effects in apoptosis assays. The compounds did not show significant toxicity in human bone marrow cells derived from healthy donors. Compound102 overcame resistance to PKC412 within a non-myelotoxic dose-range. Western Blotting experiments of 32D-FLT3-ITD cells showed dose-dependent dephosphorylation of FLT3-ITD and of its downstream targets STAT5, AKT and ERK upon incubation with either compound. In conclusion, bis(1H-indol-2-yl)methanones overcome resistance mediated by FLT3-ITD mutations at position N676 and show strong efficacy in FLT3-ITD-positive cells alone as well as in combination with chemotherapy. We propose that further development of methanone compounds overcoming resistance to currently established FLT3-TKIs is an important step forward to an anticipated need within our future therapeutic algorithm in FLT3-ITD-positive AML.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1365-2141
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
144
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
865-74
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Bis(1H-indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro.
pubmed:affiliation
Department of Haematology/Oncology, Otto-von-Guericke University, Magdeburg, Germany.
pubmed:publicationType
Journal Article