XTractor Premium

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XTractor Premium
http//www.xtractor.in/premium
A platform for discovery, knowledge sharing,
analysis and modelling of published biomedical
facts updated with manually annotated scientific
information from PubMed every single day
A Product of Molecular Connections,
INDIA www.molecularconnections.com
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CASE STUDY 2- Understanding multiple target
preferences of Imatinib (Gleevec)
Contact us 91 80- 4120 5016xtractorpremium_at_mol
ecularconnections.com
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Study Objective

• Objective 1 To study the effect of Imatinib
  (Gleevec) on CML
• Objective 2 To understand the multi-target
  preferences for Imatinib
• Capabilities demonstrated using Semantic search
  utility in XTractor
• Total analysis Time- 15 mins

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Semantic Search

• Step 1 Begin Search based on Leukemia
• Step 2 Select Leukemia, Myelogenous, Chronic,
  BCR-ABL Positive and
• Leukemia, Myeloid, Chronic-Phase from the listed
  associated terms

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Semantic Search

• Step 3 Check for all the actively studied drugs
  on Leukemia
• Step 4 Imatinib (Gleevec) happens to be one of
  the most widely used drugs against Leukemia
• Step 5 Add Imatinib to the query

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Protein Family Filter

• Now I would want to know the major protein
  families that are targeted by Imatinib
• Step 6
• Select imatinib (check box)
• Step 7
• Select Protein Family from the menu

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Major class Kinases

• The major protein families that are involved in
  association with Imatinib include Kinases and
  Phosphatases
• Step 8
• Select Protein Kinases and PTPs and add them to
  query

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Concept Linking

• Step 9
• Select Concept Linking from the Network menu
• Step 10
• Click on view sentences to get sentences for
  Imatinib and the other kinase targets

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Imatinib, BCR-Abl and CML
XTractor facts

• 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 (922), 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-gtABL kinase domain (KD) mutations are
  detected in approximately 45 of patients with
  imatinib-gtresistant 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-gtexpressing cells towards apoptotic
  death.

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Imatinib, BCR-Abl and CML
XTractor facts

• Manufactured by
• Imatinib mesylate (Gleevec, Novartis, Basel,
  Switzerland) is a small-molecule tyrosine kinase
  inhibitor with activity against ABL, BCR-ABL,
  c-KIT, and PDGFRalpha.
• Mechanism
• Bcr-gtAbl, 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 gtenhances 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.
• Translocation Junctions
• The vast majority of chronic myeloid leukemia
  (CML) patients express the BCR-gtABL transcript
  with the b2a2 (e13a2) and/or b3a2 (e14a2)
  junctions.

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Does Imatinib act on Other Protein targets as
well?
XTractor facts
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Imatinib targets macrophage colony-stimulating
factor (M-CSF) receptor
XTractor facts

• 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.
• Interesting revelation
• Imatinib is also used in breast cancer studies

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Imatinib targets PDGFR and cKIT
XTractor facts

• 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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XTractor demonstration of drug reusability
studies
Chronic Myeloid Leukemia
Bcr- Abl
Abl
PDGFR
Imatinib
M-CSF receptor

• Imatinib (Gleevec) is used as a first line
  treatment for CML.
• Imatinib is also found to have multi-target
  preference- also binds to Abl, MCSF reeptor,
  PDGFR, c-KIT

C-KIT
XTractor facts
Imatinib is also used for Breast Neoplasms,
GISTs, neuroblastoma, ALL and CML.
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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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Contact

• For a FREE Trial access http//www.xtractor.in/tr
  ial.do
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