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Objective 1: To study the effect of Imatinib (Gleevec) on CML
Objective 2: To understand the multi-target preferences for Imatinib
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Total analysis Time- 15 mins
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9. www.xtractor.in/premium Imatinib, BCR-Abl and CML What is the relation between Imatinib and CML?
Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL.
Imatinib mesylate (Gleevec, STI571), a selective inhibitor of a restricted number of tyrosine kinases, has been effectively used for the treatment of Philadelphia chromosome-positive leukemias and gastrointestinal stromal tumors.
Chronic myelogenous leukemia (CML) results from a translocation (9;22), which creates an immunogenically active BCR-ABL fusion protein.
Imatinib mesylate, a selective inhibitor of Abl tyrosine kinase, is efficacious in treating chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL).
BCR->ABL kinase domain (KD) mutations are detected in approximately 45% of patients with imatinib->resistant chronic myeloid leukemia.
Accordingly, p210 BCR-ABL TK inhibition by the TK inhibitor Imatinib mesylate (IM) evokes multiple events, including JNK phosphorylation at Thr(183), p38 mitogen-activated protein kinase (MAPK) phosphorylation at Thr(180), c-ABL de-phosphorylation at Ser residues involved in 14-3-3 binding and reduction of 14-3-3 sigma expression, that let c-ABL release from 14-3-3 sigma and nuclear import, and address BCR-ABL->expressing cells towards apoptotic death.
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Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor with activity against ABL, BCR-ABL, c-KIT, and PDGFRalpha.
Bcr->Abl, a constitutively active tyrosine kinase, is the cause of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemias (ALL).
BCR-ABL is known to suppress Protein Phosphatase 2A (PP2A) in CML cells.
Imatinib inhibited only Bcr-Abl-dependent Src activity.
Taken together, these data demonstrate that BCR/ABL >enhances the accumulation of DSBs and alters the apoptotic threshold in CML leading to error-prone DNA repair.
Imatinib, nilotinib and dasatinib are protein kinase inhibitors which target the tyrosine kinase activity of the Breakpoint Cluster Region-Abelson kinase (BCR-ABL) and are used to treat chronic myelogenous leukemia.
The vast majority of chronic myeloid leukemia (CML) patients express the BCR->ABL transcript with the b2a2 (e13a2) and/or b3a2 (e14a2) junctions.
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12. www.xtractor.in/premium Imatinib targets macrophage colony-stimulating factor (M-CSF) receptor Recently, it has been reported that imatinib also targets the macrophage colony-stimulating factor (M-CSF) receptor c-Fms.
Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals.
Co immunoprecipitation assays showed that imatinib inhibited the M-CSF-induced phosphorylation of c-Fms in osteoclast precursor cells as well as the PDGF-induced PDGFR phosphorylation in MDA-MB-231 human breast cancer cells.
In conclusion, these results collectively suggest that imatinib reduced bone metastases, at least in part, by inhibiting osteoclastic bone destruction through the blockade of c-Fms signals.
Imatinib is also used in breast cancer studies
13. www.xtractor.in/premium Imatinib targets PDGFR and cKIT Imatinib represents the first in a class of drugs targeted against chronic myelogenous leukemia to enter the clinic, showing excellent efficacy and specificity for Abl, Kit, and PDGFR kinases.
Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling.
The growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR beta and Akt.
Categorized Knockdown studies related to drug action:
IM was antiproliferative to LPC lines, and knockdown of c-kit reduced this response.
Imatinib mesylate has specific activity in inhibiting select tyrosine kinase receptors, including platelet-derived growth factor receptors (PDGFRs) and c-kit.
Imatinib is currently in early clinical trials as targeted therapy for relapsed neuroblastomas and other childhood solid tumors expressing platelet-derived growth factor receptors (PDGFR) or c-Kit.
Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitor, imatinib, is standard of care for patients with metastatic GIST.
There were significant increases in the phosphocontent of downstream PDGFR targets, Akt and ERK1/2 (5.3 fold and 2.4 fold, respectively), that were inhibited by PDGF immunoneutralization or by the selective PDGFR inhibitor imatinib.
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15. www.xtractor.in/premium XTractor also enables.. Target and Drug reusability studies
Understanding biological mechanisms of a disease/s
Biomarker related studies
Studying common pathways/processes across multiple diseases
Compare adverse drug effects across drugs of the same family
Identify similar polymorphism studies across diseases leading to changes in drug response
Compare closely related disease types
Study Knockouts and loss of function studies and co-relate them to drug effects
Result extrapolations/groupings – based on Protein Family and Drug class
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