Comprehensive characterization of the Published Kinase Inhibitor Set.
Jonathan M ElkinsVita FedeleMarta SzklarzKamal R Abdul AzeezEidarus SalahJowita MikolajczykSergei RomanovNikolai SepetovXi-Ping HuangBryan L RothAyman Al Haj ZenDenis FourchesEugene MuratovAlex TropshaJoel MorrisBeverly A TeicherMark KunkelEric PolleyKaren E LackeyFrancis L AtkinsonJohn P OveringtonPaul BamboroughSusanne MüllerDaniel J PriceTimothy M WillsonDavid H DrewryStefan KnappWilliam J ZuercherPublished in: Nature biotechnology (2015)
Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.
Keyphrases
- small molecule
- high throughput
- drug discovery
- papillary thyroid
- protein kinase
- cell proliferation
- endothelial cells
- squamous cell
- mass spectrometry
- genome wide
- vascular endothelial growth factor
- protein protein
- squamous cell carcinoma
- lymph node metastasis
- big data
- randomized controlled trial
- dna methylation
- young adults
- single molecule
- gene expression
- pi k akt
- data analysis