Coral: Clear and Customizable Visualization of Human Kinome Data

Metz, Kathleen S.; Deoudes, Erika M.; Berginski, Matthew E.; Jimenez-Ruiz, Ivan; Aksoy, Bülent Arman; Hammerbacher, Jeff; Gomez, Shawn M.; Phanstiel, Douglas H.

doi:10.1016/j.cels.2018.07.001

Cited by 147 publications

(142 citation statements)

References 17 publications

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“…In this perspective aPK refers to a subset of PKLs defined by fold and sequence similarity; this is distinct from the so-called “atypical protein kinases” (AKGs). These domains are typically depicted off to the side of Coral dendogram 40 and include protein kinases such as ATM and ATR as well as bromo-domains and TRIM proteins (see below).…”

Section: Resultsmentioning

confidence: 99%

“…In the analysis that follows we use this recomputed dark kinase list as the “dark kinome”. When the distribution of dark kinases is viewed using the standard Coral kinase dendrogram 40 , a remarkably even distribution is observed across subfamilies, with the exception that only eight tyrosine kinases are judged to be understudied ( Figure 3 ). In many cases light and dark kinases are intermingled on the dendrogram (e.g.…”

Section: Resultsmentioning

confidence: 99%

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A resource for exploring the understudied human kinome for research and therapeutic opportunities

Moret

Liu

Gyori

et al. 2020

Preprint

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ABSTRACTThe functions of protein kinases have been widely studied and many kinase inhibitors have been developed into FDA-approved therapeutics. A substantial fraction of the human kinome is nonetheless understudied. In this perspective, members of the NIH Understudied Kinome Consortium mine publicly available databases to assess the functionality of these understudied kinases as well as their potential to be therapeutic targets for drug discovery campaigns. We start with a re-analysis of the kinome as a whole and describe criteria for creating an inclusive set of 710 kinase domains as well as a curated set of 557 protein kinase like (PKL) domains. We define an understudied (‘dark’) kinome by quantifying the public knowledge on each kinase with a PKL domain using an automatic reading machine. We find a substantial number are essential in the Cancer Dependency Map and differentially expressed or mutated in disease databases such as The Cancer Genome Atlas. Based on this and other data, it seems likely that the dark kinome contains biologically important genes, a subset of which may be viable drug targets.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A resource for exploring the understudied human kinome for research and therapeutic opportunities

Moret

Liu

Gyori

et al. 2020

Preprint

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“…We found that 25 kinases that were profiled at Eurofins exhibited an IC50 < 150 nM, where 239 8 kinases had IC50 ≤ 10nM (Fig. 6) 6,21 . Importantly, 6 kinases with an IC50 < 100 nM are IDG dark 240 kinases (RIOK3, also dark, was not tested at Eurofins).…”

mentioning

confidence: 79%

PKIS Deep Dive Yields a Chemical Starting Point for Dark Kinases and a Cell Active BRSK2 Inhibitor

Tamir

Drewry

Wells

et al. 2020

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22The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed 23 to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011-2015 and by SGC-UNC 24 from 2015-2017. Screening this library of well-annotated, published kinase inhibitors has yielded 25 a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, 26 and provided impactful pre-clinical results. Based on kinome-wide screening results, we report a 27 thorough investigation of one PKIS compound, GW296115, as an inhibitor of several members of 28 the Illuminating the Druggable Genome (IDG) list of understudied dark kinases. Specifically, 29GW296115 validates as a potent lead chemical tool that inhibits six IDG kinases with IC50 values 30 less than 100nM. Focused studies establish that GW296115 is cell active, and directly engages 31 BRSK2. Further evaluation showed that GW296115 downregulates BRSK2-driven 32 phosphorylation and downstream signaling. 33 34 Introduction 35 PKIS was assembled to include 367 inhibitors designed, developed, and published by 36 GSK. Both physical samples as well as the selectivity and potency data for PKIS were made 37 publicly available. Compounds were chosen to provide broad coverage of the kinome, selecting 38 diversity in chemical scaffolds and avoiding over-representation of inhibitors targeting each 39 kinase. The composed set was distributed as a physical plate of DMSO stock solutions to all 40 interested investigators free of charge 1 . 41The National Institutes of Health (NIH) recently defined a list of proteins labeled as 42 dark/understudied due to a lack of research and reagents to characterize their function. The IDG 43 program was initiated to stimulate exploration of the role of these dark proteins in mediating 44 disease initiation and propagation with the goal of providing IDG-related therapeutic avenues. 45One category of IDG dark proteins is kinases, where a list of 162 dark kinases was curated by 46 the NIH and included in the IDG call for applications. 48the oxidative stress responsive transcription factor NRF2 (nuclear factor erythroid-2-related factor 49 2) 2 . We have reported that overexpression of active BRSK1 or BRSK2 downregulates NRF2 50 protein levels by suppressing protein translation. Focused experiments revealed that BRSK2 51 inhibits MTOR signaling while inducing phosphorylation of AMPK substrates 2 . Although 52 overexpression experiments have demonstrated the importance of BRSK2 in cell signaling, to 53 date, there are no reported small molecule inhibitors to characterize BRSK2 function in cells. 54Therefore, identifying compounds that target this kinase can yield instrumental insights into 55 BRSK2 function. 56Part of our remit for the IDG program is the creation or identification of cell active chemical 57 tools that enable the study of dark kinases. We have taken advantage of public and internal 58 datasets to look for potential inhibitors of IDG kinases. Through analysis of the PKIS data we 59 identified G...

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“…For every phosphorylated protein site, the functional score (Fig 5a), sift scores of alanine mutant (Fig 5b), the average sift scores of all variants, protein domains (Fig 4c), and kinase substrate motifs (Fig 5d) were retrieved from the previous report 11 . Kinase family tree (Fig 5c) was depicted by Coral (http://phanstiel-lab.med.unc.edu/CORAL/) 58…”

Section: Bioinformatics Analysesmentioning

confidence: 99%

Global impact of phosphorylation on protein endurance

et al. 2020

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Post-translational modifications such as phosphorylation can have profound effects on the physicochemical and biological properties of proteins. However, high-throughput and systematic approaches have not yet been developed to assess the effects of specific modification types and sites on protein lifetime, which represents a key parameter for understanding signaling rewiring and drug development. Here we describe a proteomic method, DeltaSILAC, to quantify the impact of site-specific phosphorylation on the endurance of thousands of proteins in live cells. Being configured on the reproducible data-independent acquisition mass spectrometry (DIA-MS), the pulse labeling approach using stable isotope-labeled amino acids in cells (SILAC), together with a novel peptide-level matching strategy, this multiplexed assay revealed the global delaying effect of phosphorylation on protein turnover in growing cancer cells. Further, we identified local sequence and structural features in proximity to the phosphorylated sites that could be associated with protein endurance alterations. We found that phosphorylated sites accelerating protein turnover are functionally selected for cell fitness and evolutionarily conserved. DeltaSILAC provides a generalizable approach for prioritizing the effects of phosphorylation sites on protein lifetime in the context of cell signaling and disease biology, which is highly complementary to existing methods. Finally, DeltaSILAC is widely applicable to diverse posttranslational modification types and different cell systems.

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Coral: Clear and Customizable Visualization of Human Kinome Data

Cited by 147 publications

References 17 publications

A resource for exploring the understudied human kinome for research and therapeutic opportunities

A resource for exploring the understudied human kinome for research and therapeutic opportunities

PKIS Deep Dive Yields a Chemical Starting Point for Dark Kinases and a Cell Active BRSK2 Inhibitor

Global impact of phosphorylation on protein endurance

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