Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hematopoietic class III receptor tyrosine kinase (RTK) Flt3 (Flk2, STK1) has recently received much attention as a potential drug target. Activation of Flt3 by different types of mutations plays an important role for proliferation, resistance to apoptosis, and prevention of differentiation of leukemic blasts in acute myeloid leukemia (AML). At least one type of such mutations - an internal tandem duplication in the Flt3 juxtamembrane domain (Flt3-ITD) - has been associated with an unfavorable prognosis. Signal transduction of Flt3 involves activation of several conserved pathways, including the RAS/MAP-Kinase and the phosphoinositide-3-kinase/Akt signaling cascades. Transforming versions of Flt3 exhibit altered signaling, for example a very pronounced activation of STAT5, ultimately resulting in alternate profiles of gene expression and cell transformation. Selective inhibitors of Flt3 tyrosine kinase activity have the potential to suppress aberrant Flt3 signaling. Although highly homologous to other class III RTKs, Flt3 is resistant to the phenylaminopyrimidine STI571 (Gleevec, Imatinib), a potent inhibitor of other RTKs in the family, such as the PDGFbeta-receptor or c-Kit. STI571 binding to Flt3 is prevented by the phenylalanine 691 side-chain in the ATP binding center and mutating this site to threonine renders the corresponding Flt3 mutant sensitive to STI571. Compounds of several other structural families, including the quinoxaline AG1296, the bis(1H-2-indolyl)-1-methanone D-65476, the indolinones SU5416 and SU11248, the indolocarbazoles PKC412 and CEP-701, and the piperazonyl quinazoline CT53518, are potent inhibitors of Flt3 kinase. They exhibit different selectivity profiles, both with respect to other kinases and among wildtype Flt3 and its activated versions. These compounds hold promise as novel drugs against AML and as probes for understanding activation mechanisms and signaling pathways in the class III RTK family.
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PMID:Flt3 receptor tyrosine kinase as a drug target in leukemia. 1518 May 25

Ligand-mediated activation of the FMS-like tyrosine kinase-3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. FLT3 expression in the bone marrow is restricted to CD34(+) cells and a subset of dendritic precursors. FLT3, as a member of the type III RTK subfamily, is closely related to c-kit, c-FMS, and PDGFalpha/beta and is an unspecific target of tyrosine kinase inhibitors, such as imatinib. Activating mutations of FLT3 play an important role in leukemogenesis and their presence is associated with poor prognosis in acute myeloid leukemia (AML). Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is a promising therapeutic option in the treatment of AML patients. CEP-701 (Lestaurtinib), an indocarbazole derivate, is an FLT3 tyrosine kinase inhibitor. In this study, we investigated the effect of FLT3 kinase inhibition on normal hematopoietic stem and progenitor cells in vitro. FLT3 inhibition in normal CD34(+) cells resulted in a dose-dependent inhibitory effect in cell expansion. In contrast, progenitor cell function remained nearly unaffected. Blocking the FLT3 ligand by a neutralizing antibody partially restored the effects of FLT3 inhibition. These findings might explain hematotoxicity of tyrosine kinase inhibitors such as imatinib.
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PMID:Effect of FLT3 inhibition on normal hematopoietic progenitor cells. 1744 79