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  • Perspective
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Selectivity and therapeutic inhibition of kinases: to be or not to be?

Nature Immunology volume 10, pages 356–360 (2009)Cite this article

Abstract

Protein kinases, which serve critical functions in signaling pathways in all cells, are popular therapeutic targets. At present, eight kinase inhibitors have been approved in the United States, each of which shows nanomolar potency. Although the initial goal was to generate inhibitors with a high degree of selectivity, recent experience has revealed that many of these approved compounds target more than one kinase. Surprisingly, this promiscuity is less problematic than one would have imagined; indeed, it opens new therapeutic opportunities. In this Perspective, we discuss the present status of Janus kinase inhibitors—a new class of immunosuppressive drugs—and the advantages and disadvantages of selectively inhibiting this class of kinase.

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Figure 1: The kinome binding maps of seven of the eight FDA-approved kinase inhibitors (sunitinib, sorafenib, imatinib, dasatinib, erlotinib, gefitinib and lapatinib), compared to the pan-inhibitor staurosporine (which affects more than 250 kinases) and to the investigational protein kinase inhibitors CP-690550 and VX-680.
Figure 2: Targeting cytokine signaling pathways using Jak inhibitors.

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Authors and Affiliations

  1. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Kamran Ghoreschi, Arian Laurence & John J O'Shea

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  1. Kamran Ghoreschi
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  2. Arian Laurence
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  3. John J O'Shea
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Correspondence to Kamran Ghoreschi or John J O'Shea.

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Competing interests

The US National Institutes of Health and J.J.O. hold a patent related to Janus family kinases and identification of immune modulators, and have a Collaborative Research Agreement and Development Award with Pfizer.

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Ghoreschi, K., Laurence, A. & O'Shea, J. Selectivity and therapeutic inhibition of kinases: to be or not to be?. Nat Immunol 10, 356–360 (2009). https://doi.org/10.1038/ni.1701

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