Measuring and interpreting the selectivity of protein kinase inhibitors

Smyth, Lynette A.; Collins, Ian

doi:10.1007/s12154-009-0023-9

Cited by 168 publications

(136 citation statements)

References 146 publications

(186 reference statements)

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“…Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer [5]. Indeed, several families of protein kinases orchestrate the complex events that drive the cell cycle, and their activity is frequently deregulated in hyperproliferative cancer cells [6].…”

Section: Kinases and Cancermentioning

confidence: 99%

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

Lamoral-Theys¹,

Pottier

Dufrasne³

et al. 2010

CMC

124

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Over eleven hundred publications reporting anticancer activities of polyphenols have appeared in the peerreviewed literature. In addition, a search of the PubMed database using "polyphenols -cancer -review" as keywords produced over 320 hits for review articles (July 2009). Polyphenol anticancer activities include, among others, anti-oxidative, pro-apoptotic, DNA damaging, anti-angiogenic, and immunostimulatory effects. Targeting specific protein kinases to combat cancer represents a major focus of oncology research within the so-called targeted therapy approach. An exhaustive search of the PubMed database (July 2009) using "polyphenols -cancer -kinases" as keywords resulted in more than 130 hits, half of them having been published within the past five years. Furthermore, the PubMed database contains 25 reviews on the subject of anti-kinase activity of some specific polyphenols, including mainly curcumin and the green tea polyphenol (-)-epigallocatechin 3-gallate (EGCG). However, no attempt has been made yet to review this area of research in a comprehensive, general manner. The current review therefore aims to highlight those anticancer polyphenols that target specific kinases in various types of cancer. The present review also provides an in-depth analysis of polyphenol structure-activity relationships in relation to their anticancer activities and specific kinase targeting. Lastly, a number of polyphenols are identified as potential antitumor agents that could be used to combat biologically aggressive cancers, including metastasizing cancers, through the targeting of specific kinases.

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Section: Kinases and Cancermentioning

confidence: 99%

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

Lamoral-Theys¹,

Pottier

Dufrasne³

et al. 2010

CMC

124

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“…These assays are highly specific for Mps1, but hard to quantify. Another more recently demonstrated way of measuring Mps1 kinase activity is a mobility shift assay described by Naud et al [5]: phosphorylated and non-phosphorylated peptides are separated by electrophoresis based on their charges [14]. This mobility shift assay has been compared with a radiometric assay and found to be more robust [21].…”

Section: Cc-by-nc-nd 40 International License Not Peer-reviewed) Is mentioning

confidence: 99%

“…The development of drug resistance in cancer cells is often the consequence of mutations of the targeted kinases [14]. These mutations are typically found in the ATP binding pocket, which renders the binding of inhibitors suboptimal, while retaining kinase activity [15].…”

Section: Introductionmentioning

confidence: 99%

Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures

Hiruma

Koch

Hazraty

et al. 2017

Preprint

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Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signalling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described. Here we characterize the interactions of two such mutants, Mps1 C604Y and C604W, which raise resistance to two closely related compounds, NMS-P715 and its derivative Cpd-5, but not to the well-characterised Mps1 inhibitor, reversine. We show that estimates of the IC50 (employing a novel specific and efficient assay that utilizes a fluorescently labelled substrate) and of the binding affinity (KD) indicate that in both mutants, Cpd-5 should be better tolerated than the closely related NMS-P715. To gain further insight, we determined the crystal structure of the Mps1 kinase mutants bound to Cpd-5 and NMS-P715, and compare the binding modes of Cpd-5, NMS-P715 and reversine. The difference in steric hindrance between Tyr/Trp604 and the trifluoromethoxy moiety of NMS-P715, the methoxy moiety of Cpd-5, and complete absence of such a group in reversine, account for differences we observe in vitro. Our analysis enforces the notion that inhibitors targeting Mps1 drug-resistant mutations can emerge as a feasible intervention strategy based on existing scaffolds, if the clinical need arises.Summary statementThe inhibition of specific Mps1 kinase inhibitors towards the wild-type protein and inhibitor-resistant mutants is explained by a novel specific activity assay, biophysical characterisation, and X-ray structures.AbbreviationsATPadenosine triphosphateBub1/Bub3budding uninhibited by benzimidazoles 1 / budding uninhibited by benzimidazoles 3Cpd-5Compound-5 (N-(2,6-diethylphenyl)-8-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide)FPfluorescence polarizationGSTGlutathione S-transferaseIC50half maximal inhibitory concentrationKDdissociation constantΔGcalccalculated Gibbs energy difference for ligand bindingKNL1kinetochore null protein 1KPi(inorganic) potassium phosphateMps1monopolar spindle 1MSTmicroscale thermophoresisNMS-P715N-(2,6-diethylphenyl)-1-methyl-8-({4-[(1-methylpiperidin-4-yl)carbamoyl]-2-(trifluoromethoxy)phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamideTMRtetramethylrhodamineWTwild-type

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“…In this case, the user can run the sigmoidal pipeline where the four-parameter log-logistic (Ritz et al, 2015) model is applied (Table 2). Here, the p values of the model parameters (min, max, slope, RB 50 ) will be computed to rank proteins based on their selectivity profile (Smyth & Collins, 2009 (2015) corresponds to the ratio (r) of the proteins enriched in the second incubation (supernatant) versus those retained in the first incubation (DMSO or blank) with the affinity matrix. This pulldown of pulldown or depletion factor (r) enables the calculation of a K d for each protein and it will be part of DOSCHEDA's outputs.…”

Section: Statistical Analysesmentioning

confidence: 99%

DOSCHEDA: a web application for interactive chemoproteomics data analysis

Contrino

Miele

Tomlinson

et al. 2017

PeerJ Computer Science

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Background. Mass Spectrometry (MS) based chemoproteomics has recently become a main tool to identify and quantify cellular target protein interactions with ligands/drugs in drug discovery. The complexity associated with these new types of data requires scientists with a limited computational background to perform systematic data quality controls as well as to visualize the results derived from the analysis to enable rapid decision making. To date, there are no readily accessible platforms specifically designed for chemoproteomics data analysis. Results. We developed a Shiny-based web application named DOSCHEDA (Down Stream Chemoproteomics Data Analysis) to assess the quality of chemoproteomics experiments, to filter peptide intensities based on linear correlations between replicates, and to perform statistical analysis based on the experimental design. In order to increase its accessibility, DOSCHEDA is designed to be used with minimal user input and it does not require programming knowledge. Typical inputs can be protein fold changes or peptide intensities obtained from Proteome Discover, MaxQuant or other similar software. DOSCHEDA aggregates results from bioinformatics analyses performed on the input dataset into a dynamic interface, it encompasses interactive graphics and enables customized output reports. Conclusions. DOSCHEDA is implemented entirely in R language. It can be launched by any system with R installed, including Windows, Mac OS and Linux distributions. DOSCHEDA is hosted on a shiny-server at https://doscheda.shinyapps.io/doscheda and is also available as a Bioconductor package (http://www.bioconductor.org/).

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Measuring and interpreting the selectivity of protein kinase inhibitors

Cited by 168 publications

References 146 publications

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures

DOSCHEDA: a web application for interactive chemoproteomics data analysis

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