Browse
Submit Data
Databases
API
Help

Dataset Information

313 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bantscheff-2007-1 - Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

ABSTRACT: Not available

INSTRUMENT(S): LTQ Orbitrap, LCQ Deca, instrument model, Q-Tof micro, LTQ, Waters instrument model

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Placenta, K-562 Cell, Jurkat Cell, Hela Cell

SUBMITTER: Bernhard Kuester

PROVIDER: PRD000032 | Pride | 2007-08-26

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	PRIDE_Exp_Complete_Ac_2445.pride.mgf.gz	Mgf
	PRIDE_Exp_Complete_Ac_2445.pride.mztab.gz	Mztab
	PRIDE_Exp_Complete_Ac_2445.xml.gz	Xml
	PRIDE_Exp_Complete_Ac_2446.pride.mgf.gz	Mgf
	PRIDE_Exp_Complete_Ac_2446.pride.mztab.gz	Mztab

Items per page:

1 - 5 of 2194

Publications

Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors.

Bantscheff Marcus M Eberhard Dirk D Abraham Yann Y Bastuck Sonja S Boesche Markus M Hobson Scott S Mathieson Toby T Perrin Jessica J Raida Manfred M Rau Christina C Reader Valérie V Sweetman Gavain G Bauer Andreas A Bouwmeester Tewis T Hopf Carsten C Kruse Ulrich U Neubauer Gitte G Ramsden Nigel N Rick Jens J Kuster Bernhard B Drewes Gerard G

Nature biotechnology 20070826 9

We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their ta ...[more]

PMID: 17721511

Similar Datasets

Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors.

Project description:Chronic myeloid leukemia is increasingly viewed as a chronic illness; most patients have a life expectancy close to that of the general population. Despite progress made using BCR-ABL1 tyrosine kinase inhibitors (TKIs), drug resistance via BCR-ABL1-dependent and BCR-ABL1-independent mechanisms continues to be an issue. BCR-ABL1-dependent resistance is primarily mediated through oncoprotein kinase domain mutations and usually results in overt resistance to TKIs. However, BCR-ABL1-independent resistance in the setting of effective BCR-ABL1 inhibition is recognized as a major contributor to minimal residual disease. Efforts to eradicate persistent leukemic stem cells have focused on combination therapy.

| S-EPMC5505321 | biostudies-literature

Target Landscape of Clinical Kinase Inhibitors

Project description:Here, we provide a comprehensive overview of the selectivity profiles of 242 kinase inhibitors currently in clinical trials. We screened available inhibitors against human protein kinases by using the Kinobead technology resulting in a drug matrix identifying the druggable kinome and related proteins.

2018-01-12 | MSV000081932 | MassIVE

Target Landscape of Clinical Kinase Inhibitors

2017-12-01 | PXD005336 | Pride

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Project description:The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers. Since then, there has been significant advances in our understanding of the mechanisms behind sensitization of tumors to PARP inhibitors and expansion of the use of PARPi to treat several other cancer types. Here, we review the recent advances in the proposed mechanisms of action of PARPi, biomarkers of the tumor response to PARPi, clinical advances in PARPi therapy, including the potential of combination therapies and mechanisms of tumor resistance.

| S-EPMC7509090 | biostudies-literature

Using Bcr-Abl to examine mechanisms by which abl kinase regulates morphogenesis in Drosophila.

Project description:Signaling by the nonreceptor tyrosine kinase Abelson (Abl) plays key roles in normal development, whereas its inappropriate activation helps trigger the development of several forms of leukemia. Abl is best known for its roles in axon guidance, but Abl and its relatives also help regulate embryonic morphogenesis in epithelial tissues. Here, we explore the role of regulation of Abl kinase activity during development. We first compare the subcellular localization of Abl protein and of active Abl, by using a phosphospecific antibody, providing a catalog of places where Abl is activated. Next, we explore the consequences for morphogenesis of overexpressing wild-type Abl or expressing the activated form found in leukemia, Bcr-Abl. We find dose-dependent effects of elevating Abl activity on morphogenetic movements such as head involution and dorsal closure, on cell shape changes, on cell protrusive behavior, and on the organization of the actin cytoskeleton. Most of the effects of Abl activation parallel those caused by reduction in function of its target Enabled. Abl activation leads to changes in Enabled phosphorylation and localization, suggesting a mechanism of action. These data provide new insight into how regulated Abl activity helps direct normal development and into possible biological functions of Bcr-Abl.

| S-EPMC2174184 | biostudies-literature

Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations.

Project description:The therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free-energy calculations to predict how kinase mutations modulate inhibitor affinities to Abl, a major target in chronic myelogenous leukemia (CML). We find these calculations can achieve useful accuracy in predicting resistance for a set of eight FDA-approved kinase inhibitors across 144 clinically-identified point mutations, achieving a root mean square error in binding free energy changes of 1.10.91.3 kcal/mol (95% confidence interval) and correctly classifying mutations as resistant or susceptible with 888293% accuracy. Since these calculations are fast on modern GPUs, this benchmark establishes the potential for physical modeling to collaboratively support the rapid assessment and anticipation of the potential for patient mutations to affect drug potency in clinical applications.

| S-EPMC6110136 | biostudies-literature

Comparative analysis of BCR-ABL tyrosine kinase inhibitors in BCR-ABL positive K562 cells

Project description:Tyrosine kinase activity is the crucial enzymatic activity driving all known functions of the BCR-ABL protein and is required for protection from apoptosis by BCR-ABL, therefore, targeting this enzyme is an effective approach for therapeutic strategies. Recently, a novel structural entity, imatinib (STI571; Novartis, Basel, Switzerland), a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL, has shown promise against Ph-positive leukemia in human clinical trials. However, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for overriding chemotherapy to eradicate this disease. AMN107 and BMS-354825 are clinically active “next-generation” BCR-ABL inhibitors. One potentially powerful approach is to use these compounds in combination with imatinib. The rationale for such approaches is that an inhibitor cocktail may target the widest range of resistant clones and thereby delay the onset of acquired drug resistance. More potent BCR-ABL inhibitors would be to target residual leukemia that persists in patients in whom imatinib induces durable remission but failed to eradicate the disease. From these points, our studies are performed to determine (1) the differences of molecular signaling pathways between BMS-354825 and imatinib (2) the mechanisms by which drug resistance of BMS-354825 and imatinib occur except for point mutation of BCR-ABL kinase domain. Keywords: drug sensitivity

2006-03-31 | GSE2810 | GEO

Dual-Action Kinase Inhibitors Influence p38α MAP Kinase Dephosphorylation.

Project description:Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase towards the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38α ΜΑP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we discovered three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are "dual-action" inhibitors that simultaneously block the active site and stimulate p38α dephosphorylation. Our X-ray crystal structures of phosphorylated p38α bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38α reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a new approach to achieving improved potency and specificity for therapeutic kinase inhibitors.

| S-EPMC11326130 | biostudies-literature

Aquired resistance mechanisms to EGFR-specific kinase inhibitors using chemical proteomics

Project description:Here we used kinase affinity enrichment (Kinobeads) and intensity-based mass spectrometry to elucidate aquired resistance mechanisms to EGFR inhibition in cancer cells. First, kinase expression differences between untreated control cells and long term treated resistant cells were investigated using Kinobeads and LC-MS/MS. Overexpressed Kinases were then further investigated by cellular assays to evaluate targets and development of combination treatment strategies.

2015-05-20 | PXD001825 | Pride

Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance.

Project description:Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM(R)) BCR/ABL kinase variants. Both compounds potently inhibit most IM(R) variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM(R)-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.

| S-EPMC1482597 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data