Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PI-103 KINOMEscan

ABSTRACT: For the panel of kinases, the Kd is measured using 11 serial threefold dilutions of PI-103.

SUBMITTER: Mindy Davis

PROVIDER: LDS-1148 | LINCS | 2016-06-03

REPOSITORIES: LINCS

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	HMS_LINCS&file=LDS-1148.tar.gz	Other

Items per page:

1 - 1 of 1

Publications

Comprehensive analysis of kinase inhibitor selectivity.

Davis Mindy I MI Hunt Jeremy P JP Herrgard Sanna S Ciceri Pietro P Wodicka Lisa M LM Pallares Gabriel G Hocker Michael M Treiber Daniel K DK Zarrinkar Patrick P PP

Nature biotechnology 20111030 11

We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadl ...[more]

PMID: 22037378

Similar Datasets

Determining MELK inhibitor specificity using MIB/MS

Project description:The key objectives of this study were to evaluate the selectivity profiles of three MELK inhibitors, 8a, HTH, and OTS, using a cell-based assay, in order to identify a highly selective inhibitor to subsequently investigate MELK function. To this end, we utilized a chemical proteomics approach called multiplexed kinase inhibitor beads/mass spectrometry (MIB/MS) to characterize the selectivity of these MELK inhibitors in TNBC cells.

2020-01-09 | PXD016022 | Pride

The landscape of phospho-tyrosine mediated protein interactions of human receptor tyrosine kinases

Project description:Systematically profiling the interactome of 1,144 unique wild-type and mutant phosphotyrosine residues of receptor tyrosine kinases by affinity enrichment - mass spectrometry (AE-MS), followed by a subset of novel interactors validation by competition assay.

2022-10-06 | PXD015927 | Pride

Identification of phosphorylation sites of purified ORP8 from in vitro AMPK kinase assay

Project description:We investigated the potential role of AMPK in the phosphorylation of ORP8.In vitro kinase assay using purified ORP8 and kinase-active AMPK complex confirmed that ORP8 is the direct substrate of AMPK. Phosphorylated ORP8 from in vitro kinase assay was analyzed by HPLC-MS/MS.

2023-10-24 | PXD036201 | Pride

SMARCA4_Phosphopeptide

Project description:Cyclin-Dependent Kinase 9 (CDK9) as part of the PTEFb complex promotes transcriptional elongation by promoting RNAPII pause release. We now report that, paradoxically, CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell screen, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression and cell differentiation, along with activation of endogenous retrovirus (ERV) genes. CDK9 inhibition dephosphorylates the SWI/SNF protein SMARCA4 and represses HP1α expression, both of which contribute to gene reactivation. Based on gene activation, we developed the highly selective and potent CDK9 inhibitor MC180295 (IC50 =5nM) that has broad anti-cancer activity in-vitro and is effective in in-vivo cancer models. Additionally, CDK9 inhibition sensitizes with the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.

2020-05-26 | PXD009573 | Pride

FIRST ATTEMPT TO COUPLE PROTEOMIC WITH AhR REPORTER GENE BIOASSAY IN SOIL POLLUTION MONITORING AND ASSESSMENT

Project description:A topsoil sample obtained from a highly industrialized area was tested on CALUX® cell line and exposed cells processed with proteomic and bioinformatics analyses. GC-MS/MS analysis of topsoil extracts was also performed to confirm PCDD, PCDF and dl-PCBs presence. CALUX® and GC-MS/MS data confirmed the presence of PCDD/Fs and dl-PCBs in the topsoil extract. Proteomic analysis of the cells exposed to the soil extracts identified 43 differential proteins. Enrichment analysis highlights biological processes such as cellular response to chemical stimulus, to stress, response to inorganic substance, regulation of translation, regulation of apoptotic process as well as response to organonitrogen compounds in light of particular drugs and compounds, extrapolated by bioinformatics and linked to the identified proteins modifications. These results confirm the complex epidemiological situation occurring among Taranto inhabitants and underline the need to further investigate the presence and sources of inferred chemicals in Taranto soils. The combined analysis reveals a more complex scenarios of chemicals able to affect cellular pathways and leading to toxicities rather than those identified by the bioassay. The approach to couple proteomic to CALUX® is a promising tool and deserves further investigation to be applied in soil pollution monitoring and risk assessment.

2022-02-17 | PXD027074 | Pride

Discovery of dedicated EPHA2 inhibitors - Medicinal chemistry meets chemical proteomics

Project description:The receptor tyrosine kinase EPHA2 has gained interest as therapeutical drug target in cancer and infectious diseases in the past years. However, EPHA2 research and EPHA2 based therapies have been hampered by the lack of selective small molecule EPHA2 inhibitors. We report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as lead structure. We designed hybrid structures of Dasatinib, CHEBI-513815, PD-173955 and a known EPHB4 inhibitor aiming at the exploitation of the ATP pocket entrance and the ribose pocket. Medicinal chemistry and inhibitor design was guided by a chemical proteomic approach allowing for early selectivity profiling of the newly synthesized inhibitor candidates. Additionally, protein crystallography delivered detailed insight into the molecular interactions that consitute structure-affinity-relationships. Finally, the anti-proliferative effect of the inhibitor candidates was confirmed in the glioblastoma cell line SF-268. In this work, we discovered a novel EPHA2 inhibitor candidate 4a comprising an improved selectivity profile while maintaining potency against EPHA2 and anti-cancer activity in SF-268 cells.

2017-05-30 | PXD006193 | Pride

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.

2017-12-01 | PXD005336 | Pride

Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors

Project description:Protein kinases are key components in signal transduction pathways and are established drug targets in oncology. Consequently, small molecule kinase inhibitors are on the rise but often show a rather broad target spectrum, potentially leading to toxic side effects. As a result, a broad assessment of the target space is desirable for proper interpretation of observed biological effects. The enzyme Ferrochelatase (FECH), which catalyzes the conversion of protoporphyrin IX into heme, was recently found to be an off-target of the BRAF inhibitor Vemurafenib potentially explaining the often severe phototoxicity associated with this drug in melanoma patients. However, the extent to which kinase inhibitors bind to FECH in general is currently unclear. Here, we used a chemical proteomics approach based on the kinobead technology to profile 226 clinical kinase inhibitors for their potential to bind FECH. Surprisingly, low or sub-micromolar FECH binding was detected for 29 (13%) of all compounds tested and isothermal dose response measurements confirmed drug binding to FECH in cells. We also show that Vemurafenib, Linsitinib, Neratinib and MK-2461 reduce heme levels in K562 cells, verifying that drug binding leads to loss of FECH activity. Further experiments identified the protoporphyrin pocket in FECH as one major binding site for small molecule inhibitors. Since genetic loss of FECH function leads to photosensitivity in humans, we suggest that FECH inhibition by kinase inhibitors is the molecular mechanism triggering photosensitivity in patients and should therefore be part of the pre-clinical tox package for kinase inhibitors.

2017-03-22 | PXD003373 | Pride

Chlamydomonas reinhardtii transcriptional responses to cerium dioxide nanoparticles

Project description:Agilent gene expression microarrays (Bham Chlamydomonas reinhardtii Agilent-029192 15k v1) were used to profile transcriptional changes afeter exposure of Chlamydomonas reinardtii algae to cerium dioxide nanoparticles.

2014-09-01 | E-MTAB-2454 | biostudies-arrayexpress

Extracellular ATP elicits DORN1-mediated RBOHD phosphorylation to regulate stomatal aperture

Project description:A multibillion dollar pharmaceutical industry targets purinergic signaling pathways in humans. However, in contrast, little is known about purinergic signaling in plants. Extracellular adenosine-5’-triphosphate (eATP) acts as a damage-associated molecular pattern (DAMP) in both animals and plants. The first plant eATP receptor, DORN1, was identified in Arabidopsis, defining a new kinase family (P2K) of purinoceptors. Stomates are leaf pores that control gas exchange and, therefore, impact critical functions such as photosynthesis and drought tolerance. Stomates are also the prefer entry point for leaf pathogens. The addition of ATP led to the rapid closure of Arabidopsis leaf stomates resulting in enhanced resistance to the bacterial pathogen Psuedomonas syringae. The data indicate that this response is mediated by eATP recognition by DORN1 followed by direct phosphorylation of the NADPH oxidase RBOHD, resulting in elevated production of reactive oxygen species and stomatal closure. Mutation of the DORN1 phosphorylation sites on RBOHD eliminated the ability of eATP to induce stomatal closure. To date, in contrast to work in animals, purinergic signaling in plants has been viewed as a curiosity without any direct, mechanistic connection to key plant processes. The data presented clearly demonstrates eATP as an important signal controlling stomatal aperture with important implications for the control of plant photosynthesis, water homeostasis, pathogen resistance and ultimately yield.

2018-10-24 | PXD006678 | Pride