Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

By Theonie Anastassiadis, Sean W. Deacon, Karthik Devarajan, Haiching Ma, J. R. Peterson. Nature Biotechnology, 2011

889 citations recorded by the source corpus.

Small-molecule protein kinase inhibitors are widely used to elucidate cellular signaling pathways and are promising therapeutic agents. Owing to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments that use these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we used functional assays to profile the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases. Quantitative analysis revealed complex and often unexpected interactions between protein kinases and kinase inhibitors, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can identify multitargeted inhibitors of specific, diverse kinases. The results have implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments involving kinase inhibitors.

Subfields: Computational Theory and Mathematics, Molecular Biology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/b612d88afebbd79a9ae7786ef5835ceb5ce2ff0d

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Citations in the corpus

VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. (2013, background): “Masitinib is currently the most selective TKI in clinical development or already approved to date (20, 21).”
Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “Polypharmacology is concerned with the ability of a drug binding to multiple targets, and recent studies have found that many drugs such as kinase inhibitor drugs display polypharmacology [177-181].”
Synthon-based ligand discovery in virtual libraries of over 11 billion compounds (2021, methodology): “The HotSpot radiometric assay (Reaction Biology Corporation) measures inhibition of ROCK1 catalytic activity towards a specific peptide substrate (KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK), which is monitored by P81 filter-binding methods 45 .”
STITCH 4: integration of protein–chemical interactions with user data (2013, methodology): “We import the following sources of experimental information: ChEMBL [interactions with reported K i or IC 50 (7)], PDSP K i Database (8), PDB (9) and—new to STITCH—data from two large-scale studies on kinase–ligand interactions (10,11).”
KinMap: a web-based tool for interactive navigation through human kinome data (2017, background): “The resulting phylogenetic tree is commonly used to visualize compound profiling data [4, 5] or structural features of kinases [6, 7].”
STITCH 5: augmenting protein–chemical interaction networks with tissue and affinity data (2015, background): “Other large sources of protein–chemical links are the datasets of experimentally validated interactions, which include ChEMBL (27), PDSP K i Database (28), Protein Data Bank (PDB) (29) and two high-throughput kinase–ligand interactions studies (30,31).”
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis (2014, background): “…pattern of kinase inhibition by sorafenib against 300 purified kinase domains is highly similar to that of nilotinib, masitinib, and imatinib (Anastassiadis et al., 2011), yet none of these agents appear to trigger ferroptosis, as defined by sensitivity to ferroptosis-specific cell death…”