INT273555

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Context Info
Confidence 0.57
First Reported 2008
Last Reported 2010
Negated 0
Speculated 0
Reported most in Body
Documents 17
Total Number 20
Disease Relevance 9.65
Pain Relevance 0.44

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

cytosol (Bcr) signal transduction (Bcr) plasma membrane (Bcr)
intracellular (Bcr) enzyme binding (Bcr) kinase activity (Bcr)
Anatomy Link Frequency
32D 1
arm 1
Bcr (Mus musculus)
Bcr - T315I (1)
Pain Link Frequency Relevance Heat
Potency 72 99.90 Very High Very High Very High
Pain 4 86.12 High High
backache 4 83.84 Quite High
tolerance 8 82.24 Quite High
headache 32 21.20 Low Low
pruritus 28 5.00 Very Low Very Low Very Low
Central nervous system 20 5.00 Very Low Very Low Very Low
cytokine 12 5.00 Very Low Very Low Very Low
cva 8 5.00 Very Low Very Low Very Low
abdominal pain 4 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Myeloid Leukemia 988 98.98 Very High Very High Very High
Chromosome Aberrations 32 98.76 Very High Very High Very High
Leukemia 196 98.64 Very High Very High Very High
Philadelphia Chromosome 192 94.48 High High
Toxicity 80 93.20 High High
Cancer 52 89.28 High High
Apoptosis 72 88.72 High High
Disease 156 88.64 High High
Pain 4 86.12 High High
Low Back Pain 4 83.84 Quite High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
Imatinib mesylate, a BCR-ABL TK inhibitor, is the frontline therapy for CML.
Negative_regulation (inhibitor) of BCR associated with myeloid leukemia
1) Confidence 0.57 Published 2009 Journal Therapeutics and Clinical Risk Management Section Abstract Doc Link PMC2697539 Disease Relevance 0.45 Pain Relevance 0
This approach needs to be eventually extended to include specific inhibitors of T315I Bcr-Abl kinase domain mutations.
Negative_regulation (inhibitors) of Bcr-Abl (T315I)
2) Confidence 0.57 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.12 Pain Relevance 0
Nilotinib (Tasigna®, AMN107, Novartis) is a close analog of imatinib with approximately 20-fold higher potency for BCR-ABL kinase inhibition.
Negative_regulation (inhibition) of BCR-ABL associated with potency
3) Confidence 0.57 Published 2008 Journal Drug design, development and therapy Section Abstract Doc Link PMC2761189 Disease Relevance 0.54 Pain Relevance 0.14
Nilotinib has superior potency compared with imatinib as an inhibitor of BCR-ABL in vitro and in vivo: it is 10- to 30-fold more potent, as assessed by its ability to block proliferation of BCR-ABL dependent cell lines derived from CML patients (K562, Ku-812F) and cell lines (32D or Ba/F3) transfected to express the BCR-ABL protein (Figure 2; Weisberg et al 2005).
Negative_regulation (inhibitor) of BCR-ABL in 32D associated with myeloid leukemia and potency
4) Confidence 0.48 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 0.17 Pain Relevance 0.05
A suboptimal response was defined as an incomplete hematologic response at 3 months, less than a partial cytogenetic response at 6 months, less than a complete cytogenetic response at 12 months, less than a major molecular response at 18 months, and, in the case of a major molecular response, loss of BCR-ABL, other mutations or other chromosomal abnormalities.11
Negative_regulation (loss) of BCR associated with chromosome aberrations
5) Confidence 0.42 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.27 Pain Relevance 0
Imatinib mesylate (Gleevec®; Novartis Pharma, East Hanover, NJ, USA) is a very specific inhibitor of BCR-ABL tyrosine kinase activity of the 2-phenylamino pyrimidine class, and it is approved by the Food and Drug Administration as frontline therapy for patients with CML.6 Imatinib acts by binding and stabilizing the inactive form of BCR-ABL, thereby inhibiting its autophosphorylation and the phosphorylation of its substrate, abrogating proliferation and inducing apoptosis of BCR-ABL–positive cells.4,7 The superiority of imatinib for successful clinical outcomes of patients with CML was confirmed by the International Randomized Study of Interferon plus low-dose cytarabine, the previous standard of care, vs STI571, or the imatinib (IRIS) trial, in which 553 patients were randomized to each arm.8 Imatinib induced high rates of complete hematologic response (96% at 1 year, which increased to 98% at 5 years),8 a major cytogenetic response (86% at 1 year, which increased to 92% at 5 years), a complete cytogenetic response (69% at 1 year and 87% at 5 years), a progression-free survival rate without accelerated or blast crisis (93% at 6 years), overall progression-free survival (83% at 6 years) and overall survival (95% at 6 years, taking into consideration only CML-related deaths; and 88% at 6 years when deaths from any cause were included).8–10
Negative_regulation (inhibitor) of BCR in arm associated with myeloid leukemia, blast crisis and apoptosis
6) Confidence 0.42 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 1.07 Pain Relevance 0
These include dasatinib (Sprycel®; BMS-354825, Bristol-Myers-Squibb), an orally bioavailable dual Bcr-Abl and Src inhibitor, and nilotinib (Tasigna®; AMN-107, Novartis), a potent selective Bcr-Abl inhibitor.
Negative_regulation (inhibitor) of Bcr-Abl
7) Confidence 0.42 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.49 Pain Relevance 0
Nilotinib (formerly AMN107, Novartis Pharmaceuticals, Basel, Switzerland) is an oral TKI that was developed from its parent compound, imatinib, as a more potent inhibitor of Bcr-Abl (Golemovic et al 2005; Verstovsek et al 2005).
Negative_regulation (inhibitor) of Bcr-Abl
8) Confidence 0.42 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.45 Pain Relevance 0
However, in primary CD34-CML cells, nilotinib and imatinib were equipotent for inhibition of Bcr-Abl activity.
Negative_regulation (inhibition) of Bcr-Abl associated with myeloid leukemia
9) Confidence 0.42 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.19 Pain Relevance 0.05
New TKIs are available or in development that are more potent than imatinib for inhibiting Bcr-Abl and have a decreased potential for resistance.
Negative_regulation (inhibiting) of Bcr-Abl
10) Confidence 0.42 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.45 Pain Relevance 0
These include dasatinib (Sprycel®; BMS-354825, Bristol-Myers-Squibb), an orally bioavailable dual Bcr-Abl and Src inhibitor, and nilotinib (Tasigna®; AMN-107, Novartis), a potent selective Bcr-Abl inhibitor.
Negative_regulation (inhibitor) of Bcr-Abl
11) Confidence 0.42 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.51 Pain Relevance 0
More importantly, dasatinib induced molecular responses and reduced BCR-ABL/ABL transcript ratios from 66% at baseline to 2.6% at 9 months.
Negative_regulation (reduced) of BCR
12) Confidence 0.42 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.52 Pain Relevance 0
Both nilotinib and dasatinib efficiently block Bcr-Abl tyrosine kinase catalytic activity by binding to distinct, partially overlapping sites in the kinase domain.
Negative_regulation (block) of Bcr-Abl
13) Confidence 0.42 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.13 Pain Relevance 0
Nilotinib selectively inhibits Bcr-Abl, Kit, and PDGFR tyrosine kinases, but does not significantly affect any of the kinases required for IL-3 signaling, such as JAK2, or a broad variety of other receptor tyrosine kinases or tyrosine kinase oncogenes (Weisberg et al 2005).
Negative_regulation (inhibits) of Bcr-Abl
14) Confidence 0.35 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 1.25 Pain Relevance 0
With this study a minimun dose (200 mg) required for effective BCR-ABL inhibition in imatinib-resistant/intolerant leukemia was established; the preclinical profile of nilotinib as active drug against mutant BCR-ABL was largely confirmed.
Negative_regulation (inhibition) of BCR-ABL associated with leukemia
15) Confidence 0.35 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 1.42 Pain Relevance 0.17
Jørgensen et al had reported on the efficacy of nilotinib on CD34+ CML cells: in this subset, imatinib and nilotinib were equipotent for the inhibition of BCR-ABL activity, and produced equivalent effect but incomplete reduction in CRKL phosphorylation at 5 ?
Negative_regulation (inhibition) of BCR-ABL associated with myeloid leukemia
16) Confidence 0.35 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 0.51 Pain Relevance 0
Results from in vitro studies have demonstrated that nilotinib is more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity in cell lines and that it is at least 10-to 30-fold more potent than imatinib in inhibiting proliferation of Bcr-Abl-expressing cells.
Negative_regulation (inhibiting) of Bcr-Abl
17) Confidence 0.35 Published 2010 Journal Core evidence Section Body Doc Link PMC2899790 Disease Relevance 0.15 Pain Relevance 0
Attempts to circumvent resistance led to the discovery of nilotinib (Tasigna), a novel, potent and selective oral Bcr-Abl kinase inhibitor.


Negative_regulation (inhibitor) of Bcr-Abl
18) Confidence 0.35 Published 2010 Journal Core evidence Section Abstract Doc Link PMC2899790 Disease Relevance 0.69 Pain Relevance 0
Nilotinib was developed using a rational design strategy based on the premise that Bcr-Abl inhibitors more potent and selective than imatinib could be developed by making modest changes in this molecule.15 Analysis of the structure of imatinib and that of the Abl kinase domain indicated that changes to the structure’s part that binds deep into the ATP-binding pocket would be likely to decrease its efficacy, but that modification of the methylpiperazinyl group of imatinib that lies along a partially hydrophobic group on the surface of Abl kinase might improve binding characteristics.
Negative_regulation (inhibitors) of Bcr-Abl
19) Confidence 0.35 Published 2010 Journal Core evidence Section Body Doc Link PMC2899790 Disease Relevance 0.20 Pain Relevance 0
M.15,20 Nilotinib also potently inhibited tyrosine autophosphorylation of the E255K, E255V, F317L, M351T, and F486S Bcr-Abl mutants, and these effects were not associated with decreases in Abl or Bcr-Abl protein levels.
Negative_regulation (decreases) of Bcr-Abl
20) Confidence 0.35 Published 2010 Journal Core evidence Section Body Doc Link PMC2899790 Disease Relevance 0.07 Pain Relevance 0.04

General Comments

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