INT241499

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Context Info
Confidence 0.47
First Reported 2008
Last Reported 2010
Negated 3
Speculated 0
Reported most in Body
Documents 23
Total Number 23
Disease Relevance 8.86
Pain Relevance 0.75

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

mitochondrion (Abl1) DNA binding (Abl1) cytoplasm (Abl1)
cytosol (Abl1) nucleolus (Abl1) cell adhesion (Abl1)
Anatomy Link Frequency
arm 1
platelet 1
Abl1 (Mus musculus)
Pain Link Frequency Relevance Heat
Potency 78 99.68 Very High Very High Very High
Paracetamol 17 70.64 Quite High
cINOD 5 66.92 Quite High
abdominal pain 9 47.20 Quite Low
headache 25 44.88 Quite Low
Piles 4 31.68 Quite Low
Bioavailability 17 28.00 Quite Low
adenocard 2 10.08 Low Low
antagonist 1 9.40 Low Low
Central nervous system 48 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Myeloid Leukemia 1340 99.60 Very High Very High Very High
Apoptosis 62 97.62 Very High Very High Very High
Leukemia 229 96.98 Very High Very High Very High
Solid Tumor 4 96.06 Very High Very High Very High
Cancer 136 93.40 High High
Philadelphia Chromosome 112 92.44 High High
Toxicity 132 92.04 High High
Metastasis 20 90.28 High High
Disease 241 90.20 High High
Renal Disease 5 89.44 High High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
Dasatinib binds multiple conformations of BCR-ABL [30], unlike imatinib and nilotinib [31,32].
ABL Binding (binds) of
1) Confidence 0.47 Published 2008 Journal J Hematol Oncol Section Body Doc Link PMC2567340 Disease Relevance 0.53 Pain Relevance 0.03
Such mutations inhibit the ability of imatinib to bind to BCR-ABL by corrupting the binding sites or preventing the kinase domain from assuming the inactive conformation required for imatinib binding [11].
ABL Neg (inhibit) Binding (bind) of
2) Confidence 0.35 Published 2008 Journal J Hematol Oncol Section Body Doc Link PMC2567340 Disease Relevance 0.32 Pain Relevance 0
The increased potency of dasatinib, combined with its ability to bind multiple conformation of BCR-ABL, produces significant efficacy in patients with CML and Ph+ ALL.
ABL Binding (bind) of associated with myeloid leukemia and potency
3) Confidence 0.35 Published 2008 Journal J Hematol Oncol Section Body Doc Link PMC2567340 Disease Relevance 0.42 Pain Relevance 0.05
The ability to bind both active and inactive conformations of BCR-ABL may explain its potent activity against most of the known imatinib-resistant kinase domain mutations, with the exception of T315I [33].
ABL Neg (inactive) Binding (bind) of
4) Confidence 0.35 Published 2008 Journal J Hematol Oncol Section Body Doc Link PMC2567340 Disease Relevance 0.52 Pain Relevance 0.04
Similar to imatinib, nilotinib binds to Abl in its inactive conformation.
Abl Binding (binds) of
5) Confidence 0.34 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.13 Pain Relevance 0.05
Compared with imatinib, dasatinib is more potent and binds to the active conformation of the Abl kinase domain (Figure 3, middle panel).
Abl Binding (binds) of
6) Confidence 0.30 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.12 Pain Relevance 0
This most frequently has a molecular weight of 210 kD (p210Bcr/Abl) and has increased tyrosine kinase activity which is essential to its transforming capability.1,2 Imatinib mesylate is a potent and selective tyrosine kinase inhibitor that has become standard therapy for patients with CML in all stages of the disease.2 A complete cytogenetic response (CGCR) can be achieved in 50% to 60% of patients treated in chronic phase (CP) after failure with interferon alpha (IFN-?)
Abl Binding (weight) of associated with myeloid leukemia and disease
7) Confidence 0.30 Published 2010 Journal Core evidence Section Body Doc Link PMC2899790 Disease Relevance 0.61 Pain Relevance 0
Overall, 162 patients were followed with mutational analysis: 26% retained a BCR-ABL mutation, 26% lost a mutation, 27% developed a mutation, and the remaining belonged to > 1 mutational category.24
ABL Binding (mutation) of
8) Confidence 0.30 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.24 Pain Relevance 0
Recently, dasatinib-induced BCR-ABL inhibition was shown to be sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis and suggested that in patients with CML receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy.31
ABL Neg (inhibition) Binding (inhibition) of associated with leukemia, myeloid leukemia and apoptosis
9) Confidence 0.30 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.98 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
ABL Binding (binding) of in arm associated with myeloid leukemia, blast crisis and apoptosis
10) Confidence 0.28 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.85 Pain Relevance 0
Dasatinib binds the inactive and active conformation of the ABL kinase domain, requires fewer contact points with ABL, and has a greater affinity to the ABL kinase domain compared to imatinib.
ABL Binding (binds) of
11) Confidence 0.28 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.27 Pain Relevance 0
In particular, crystal structure analysis of the Abl-imatinib complex (Figure 2) has been helpful in the identification of potential critical residues that hinder the interaction of imatinib with mutated Bcr-Abl (Schindler et al 2000).


Abl Binding (interaction) of
12) Confidence 0.26 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.14 Pain Relevance 0.04
These fascinating results may indicate the possibility to develop targeted treatment approaches interacting with Bcr-Abl-induced pathways rather than Bcr-Abl itself.
Abl Binding (interacting) of
13) Confidence 0.26 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.62 Pain Relevance 0
A model of nilotinib in complex with Abl kinase mutant M351T showed that the sensitivity of Bcr-Abl mutants to nilotinib segregates into 4 categories: high (IC50 < 70 nmol/L: M244V, G250E, Q252H, F3llL, F317L, M351T, V379I, L387M, H396P, H396R), medium (IC50 < 200 nmol/L: Y253F, E255K, F359V), low (IC50 < 450 nmol/L: Y253H, E255V), and insensitive (IC50 > 2 ?
Abl kinase Binding (complex) of
14) Confidence 0.23 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0 Pain Relevance 0.09
It was hypothesized that the potency and selectivity of imatinib could be improved by maintaining binding to the inactive conformation of the Abl kinase domain, but incorporating alternative binding groups to the N-methylpiperazine moiety, while preserving an amide pharmacophore to retain H-bond interactions to Glu286 and Asp381.
Abl kinase Binding (binding) of associated with potency
15) Confidence 0.23 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0 Pain Relevance 0.05
Like imatinib, nilotinib binds to the inactive conformation of the Abl tyrosine kinase, with p-loop folding over the ATP-binding site, and the activation-loop (involving the pyridyl-N and the backbone-NH of Met318, the anilino-NH and the side-chain hydroxyl of Thr315, the amido-NH and side-chain carboxylate of Glu286, as well as the amido-C = O and backbone-NH of Asp381) blocking the substrate binding site, to disrupt the ATP-phosphate-binding site, and inhibit the catalytic activity of the enzyme (Manley et al 2005).
Abl tyrosine kinase Binding (binds) of
16) Confidence 0.22 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0 Pain Relevance 0.04
Unlike imatinib, this drug makes only four hydrogen-bond interactions with the ABL kinase domain, involving the pyridyl-N and the backbone-NH of Met 318, the anilino-NH and the side chain hydroxyl of Thr315, the amido-NH and side chain carboxylate of Glu 286 and the amido C = O with the backbone-nh of the Asp 381 (Manley et al 2005).
ABL Binding (interactions) of
17) Confidence 0.17 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 0.14 Pain Relevance 0.08
Dasatinib was identified among a series of novel 2-(aminopyridyl)-and 2-(aminopyrimidinyl)-thiazole-5-carboxamides as a compound with broad spectrum antiproliferative activity against hematological and solid tumor cell lines, and favorable pharmacokinetics after oral dosing.11 X-ray crystallographic studies of the three-dimensional structure of Abl kinase complexed with dasatinib revealed that the compound binds to the activation loop of Abl in an active conformation.11 In addition, interactions between the Abl ATP-binding site and dasatinib were less critical for binding, suggesting that the compound would be active against the mutant kinase forms.11 Initial studies revealed that dasatinib is a potent multi-target kinase inhibitor of Bcr-Abl, SFK (Src, Lck, and Yes), PDGFR?
Abl Binding (binds) of associated with solid tumor
18) Confidence 0.15 Published 2009 Journal OncoTargets and therapy Section Body Doc Link PMC2886328 Disease Relevance 0.31 Pain Relevance 0
These compounds also inhibit Bcr-Abl, Kit and platelet-derived growth factor receptor ?
Abl Binding (compounds) of in platelet
19) Confidence 0.15 Published 2009 Journal OncoTargets and therapy Section Body Doc Link PMC2886328 Disease Relevance 0.64 Pain Relevance 0
Dasatinib was identified among a series of novel 2-(aminopyridyl)-and 2-(aminopyrimidinyl)-thiazole-5-carboxamides as a compound with broad spectrum antiproliferative activity against hematological and solid tumor cell lines, and favorable pharmacokinetics after oral dosing.11 X-ray crystallographic studies of the three-dimensional structure of Abl kinase complexed with dasatinib revealed that the compound binds to the activation loop of Abl in an active conformation.11 In addition, interactions between the Abl ATP-binding site and dasatinib were less critical for binding, suggesting that the compound would be active against the mutant kinase forms.11 Initial studies revealed that dasatinib is a potent multi-target kinase inhibitor of Bcr-Abl, SFK (Src, Lck, and Yes), PDGFR?
Abl Binding (binding) of associated with solid tumor
20) Confidence 0.15 Published 2009 Journal OncoTargets and therapy Section Body Doc Link PMC2886328 Disease Relevance 0.41 Pain Relevance 0

General Comments

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