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The (un)targeted cancer kinome

Nature Chemical Biology volume 6, pages 166–169 (2010)Cite this article

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The complexity of cancer signaling and the resulting difficulties in target selection have strongly biased kinase drug discovery towards clinically validated targets. Recently, novel kinase targets that are uncharacterized have emerged from genome sequencing and RNAi studies. Chemical probes are urgently needed to functionally annotate these kinases and to stimulate new drug discovery efforts.

Since the discovery of the first oncogene, vSrc, in the 1970s and its identification as an enzyme with tyrosine kinase activity, dysfunctional signaling by mutated or overexpressed kinases has been intimately linked to the development of cancer. However, despite strong links between kinase deregulation and the development of cancers, inhibitor development projects were initially met with skepticism. More than ten years later, potent but nonselective tool molecules such as staurosporine finally led to the initiation of drug development efforts after cellular inhibition of kinases had been demonstrated1. The approval of the first kinase inhibitor, imatinib, for the treatment of chronic myelogenous leukemia (CML) in 2001 and the success of antibody-based drugs that targeted the epidermal growth factor receptor (erbB2) in breast cancer (trastuzumab) and colon cancer (cetuximab) heralded the current period of intensive kinase drug development efforts. So far, nine small-molecule kinase inhibitors have been approved for the treatment of cancer. These inhibitors have been developed targeting specifically the kinases c-Abl (and Bcr-Abl), PDGFR, cKit, and the EGFR and VEGFR family2. However, the development of large selectivity screening platforms revealed that with the exception of the highly selective inhibitor lapatinib3, most approved kinase inhibitors have limited selectivity and target multiple kinases4,5,6. The performance of recently developed kinase inhibitors in clinical trials is surprisingly robust. A recent survey of 974 anticancer agents claims that the clinical attrition rate of kinase inhibitors from phase 1 to registration is only 53%—significantly lower than for other antitumor agents, which showed an overall attrition rate of 82%7.

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Figure 1: Kinase targets in clinical trials and the currently targeted kinome.
Figure 2: Kinase structure and inhibitor design.

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Authors and Affiliations

  1. Susanne Müller and Stefan Knapp are in the Nuffield Department of Clinical Medicine, Oleg Fedorov, Structural Genomics Consortium, University of Oxford, Oxford, UK.,

    Oleg Fedorov, Susanne Müller & Stefan Knapp

  2. Stefan Knapp is also in the Department of Clinical Pharmacology, University of Oxford, Oxford, UK.,

    Stefan Knapp

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  1. Oleg Fedorov
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  2. Susanne Müller
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Correspondence to Stefan Knapp.

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Fedorov, O., Müller, S. & Knapp, S. The (un)targeted cancer kinome. Nat Chem Biol 6, 166–169 (2010). https://doi.org/10.1038/nchembio.297

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