Research Article

The target landscape of clinical kinase drugs

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Science  01 Dec 2017:
Vol. 358, Issue 6367, eaan4368
DOI: 10.1126/science.aan4368

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An atlas for drug interactions

Kinase inhibitors are an important class of drugs that block certain enzymes involved in diseases such as cancer and inflammatory disorders. There are hundreds of kinases within the human body, so knowing the kinase “target” of each drug is essential for developing successful treatment strategies. Sometimes clinical trials can fail because drugs bind more than one target. Yet sometimes off-target effects can be beneficial, and drugs can be repurposed for treatment of additional diseases. Klaeger et al. performed a comprehensive analysis of 243 kinase inhibitors that are either approved for use or in clinical trials. They provide an open-access resource of target summaries that could help researchers develop better drugs, understand how existing drugs work, and design more effective clinical trials.

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Structured Abstract


Molecularly targeted drugs such as imatinib and crizotinib have revolutionized the treatment of certain blood and lung cancers because of their remarkable clinical success. Over the past 20 years, protein kinases have become a major class of drug targets because these signaling biomolecules are often deregulated in disease, particularly in cancer. Today, 37 small kinase inhibitors (KIs) are approved medicines worldwide and more than 250 drug candidates are undergoing clinical evaluation.


Although it is commonly accepted that most KIs target more than one protein, the extent to which this information is available to the public varies greatly between drugs. It would seem important to thoroughly characterize the target spectrum of any drug because additional off-targets may offer opportunities, not only for repurposing but also to explain undesired side effects. To this end, we used a chemical proteomic approach (kinobeads) and quantitative mass spectrometry to characterize the target space of 243 clinical KIs that are approved drugs or have been tested in humans.


The number of targets for a given drug differed substantially. Whereas some compounds showed exquisite selectivity, others targeted more than 100 kinases simultaneously, making it difficult to attribute their biological effects to any particular mode of action. Also of note is that recently developed irreversible KIs can address more kinases than their intended targets epidermal growth factor receptor (EGFR) and Bruton’s tyrosine kinase (BTK). Collectively, the evaluated KIs targeted 220 kinases with submicromolar affinity, offering a view of the druggable kinome and enabling the development of a universal new selectivity metric termed CATDS (concentration- and target-dependent selectivity). All drug profiles can be interactively explored in ProteomicsDB and a purpose-built shinyApp. Many uses of this unique data and analysis resource by the scientific community can be envisaged, of which we can only highlight a few. The profiles identified many new targets for established drugs, thus improving our understanding of how these drugs might exert their phenotypic effects. For example, we evaluated novel salt-inducible kinase 2 (SIK2) inhibitors for their ability to modulate tumor necrosis factor–α (TNFα) and interleukin-10 (IL-10) production, which may allow repurposing these drugs for inflammatory conditions. Integrating target space information with phosphoproteomic analysis of several EGFR inhibitors enabled the identification of drug response markers inside and outside the canonical EGFR signaling pathway. Off-target identification may also inform drug discovery projects using high-value clinical molecules as lead compounds. We illustrate such a case by a novel structure-affinity relationship analysis of MELK inhibitors based on target profiles and cocrystal structures. To assess the repurposing potential of approved or clinically advanced compounds, we used cell-based assays and mouse xenografts to show that golvatinib and cabozantinib may be used for the treatment of acute myeloid leukemia (AML) based on their FLT3 inhibitory activity.


This work provides a rich data resource describing the target landscape of 243 clinically tested KIs. It is the most comprehensive study to date and illustrates how the information may be used in basic research, drug discovery, or clinical decision-making.

Schematic representation of identifying the druggable kinome.

A chemical proteomic approach revealed quantitative interaction profiles of 243 clinically evaluated small-molecule KIs covering half of the human kinome. Results can be interactively explored in ProteomicsDB and inform basic biology, drug discovery, and clinical decision-making.


Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the “druggable” kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD–positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

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