The FMS-like receptor tyrosine kinase 3 (FLT3) plays an natural part
Posted by kinsxu on Tuesday, November 8, 2011
The FMS-like receptor tyrosine kinase 3 (FLT3) plays an natural part in
managing the differentiation and proliferation of hematopoietic cells.
Somaticmutations from the FLT3 have already been frequently identified
in acute myeloid leukemia. Mutations in FLT3 primarily include internal
tandem duplications (ITD) in the juxtamembrane domain, affecting 15%to
34%AML patients, or pointmutations in the tyrosine kinase domain in 8%
to 12%of patients. Thesemutations are associatedwith an awful prognosis
within adult and pediatricAML patients.Mutations bring about
autophosphorylationof the FLT3 kinase domain and, for that reason, there
exists upregulation and activation of downstream signaling pathways for
example the Ras/Raf/MEK/ERK pathway, the phosphoinositide-3 (PI3K)
kinase pathway (PI3K/PTEN/Akt/mTOR), as well as the Janus activated
kinase (JAK)/STAT pathways. Consequently,there is certainly uncontrolled
proliferation, arrest of myeloid cell differentiation, and increased
effectiveness against apoptosis. AML patients receiving conventional
chemotherapy regimens experience significant toxicity and relapse as a
result of drug resistance. Consequently, inhibitors targeting FLT3, with
lower toxicity greater potency than conventional chemotherapy, have
emerged and so are currently being investigated. Preclinical studies
with your inhibitors demonstrate a result at inhibiting proliferation
and inducing apoptosis in human FLT3 mutant cell lines. As well as, in
vitro studies on the results of FLT3
inhibitors on human leukemia cell lines with FLT3 mutations have demostrated inhibition of downstream people in the PI3K pathway including Akt, people in the Ras/Raf/MEK/ERK pathway for instance ERK1/2 andMEK1/2,members in the JAK/STAT pathway for example STAT5, and cellcycle regulators for example cyclinD, cyclin E, p21waf1/cip, and p27kip1. Furthermore, FLT3 inhibitors have been proven to affect people in the Bcl-2 group of apoptotic proteins, much like the proapoptotic proteins BAD and Bim, and antiapoptotic proteins Bcl-xl and Mcl-1. Linifanib (ABT-869) is definitely an ATP-competitive tyrosine kinase inhibitor effective against constitutively active FLT3 along with other people in the platelet-derived growth factor receptor (PDGF) and VEGF receptor VEGFR) families. Linifanib is proven, in vivo,tobe effective against AML cells harboring FLT3 mutations (MV-411), highly angiogenic fibrosarcoma, small¨Ccell lung carcinoma, epidermoid carcinoma, breast carcinoma, and colon adenocarcinoma. Treatment of AML cells with linifanibin conjunction with other FLT3 inhibitors,for example CEP-701 (lestaurtinib), or chemotherapy, for example cytosine arabinoside (Ara-C) and doxorubicin, have demostrated synergistic effects. Preclinical studies show that linifanib inhibits proliferation in FLT3 ITD¨Cpositive human leukemia cell linesMV-411 and Molm-14 at a half-maximal inhibitory concentration (IC50) of less than10nmol/L(7,10).Furthermore, linifanibcauses cell-cycle arrest and apoptosis through decreased expression of cyclinsDand E and increased expression of cyclindependent inhibitors p21waf1/cipand p27kip1. In addition, increased expression of proapoptotic BAD, BAK, and BID and decreased expression of antiapoptotic protein Bcl-xl are observed. In addition to inhibiting phosphorylation of the FLT3 receptor, linifanib has long been
consideration to come with an inhibitory result on downstreamkinases including Akt, ERK, STAT5, and Pim-1.
inhibitors on human leukemia cell lines with FLT3 mutations have demostrated inhibition of downstream people in the PI3K pathway including Akt, people in the Ras/Raf/MEK/ERK pathway for instance ERK1/2 andMEK1/2,members in the JAK/STAT pathway for example STAT5, and cellcycle regulators for example cyclinD, cyclin E, p21waf1/cip, and p27kip1. Furthermore, FLT3 inhibitors have been proven to affect people in the Bcl-2 group of apoptotic proteins, much like the proapoptotic proteins BAD and Bim, and antiapoptotic proteins Bcl-xl and Mcl-1. Linifanib (ABT-869) is definitely an ATP-competitive tyrosine kinase inhibitor effective against constitutively active FLT3 along with other people in the platelet-derived growth factor receptor (PDGF) and VEGF receptor VEGFR) families. Linifanib is proven, in vivo,tobe effective against AML cells harboring FLT3 mutations (MV-411), highly angiogenic fibrosarcoma, small¨Ccell lung carcinoma, epidermoid carcinoma, breast carcinoma, and colon adenocarcinoma. Treatment of AML cells with linifanibin conjunction with other FLT3 inhibitors,for example CEP-701 (lestaurtinib), or chemotherapy, for example cytosine arabinoside (Ara-C) and doxorubicin, have demostrated synergistic effects. Preclinical studies show that linifanib inhibits proliferation in FLT3 ITD¨Cpositive human leukemia cell linesMV-411 and Molm-14 at a half-maximal inhibitory concentration (IC50) of less than10nmol/L(7,10).Furthermore, linifanibcauses cell-cycle arrest and apoptosis through decreased expression of cyclinsDand E and increased expression of cyclindependent inhibitors p21waf1/cipand p27kip1. In addition, increased expression of proapoptotic BAD, BAK, and BID and decreased expression of antiapoptotic protein Bcl-xl are observed. In addition to inhibiting phosphorylation of the FLT3 receptor, linifanib has long been
consideration to come with an inhibitory result on downstreamkinases including Akt, ERK, STAT5, and Pim-1.