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Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

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Small-Molecule Inhibitors of Protein-Protein Interactions

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 348))

Abstract

The IL-2:IL-2R protein–protein interaction is of central importance to both healthy and diseased immune responses, and is one of the earliest examples of successful small-molecule inhibitor discovery against this target class. Drug-like inhibitors of IL-2 have been identified through a combination of fragment discovery, structure-based design, and medicinal chemistry; this discovery approach illustrates the importance of using a diverse range of complementary screening methods and analytical tools to achieve a comprehensive understanding of molecular recognition. The IL-2 story also provides insight into the dynamic nature of protein–protein interaction surfaces, their potential druggability, and the physical and chemical properties of effective small-molecule ligands. These lessons, from IL-2 and similar discovery programs, underscore an increasing awareness of the principles governing the development of drugs for protein–protein interactions.

We dedicate this manuscript to the memory of Dr Warren DeLano, who taught us how to look at structures.

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  1. Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA, 94158, USA

    C. G. M. Wilson & M. R. Arkin

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  1. Roche Research Center, Dept. Discovery Oncology, Hoffmann-La Roche Inc., Kingsland Street 340, Nutley, 07110-1199, New Jersey, USA

    Lyubomir Vassilev

  2. Roche Research Center, Dept. of Discovery Oncology, Hoffmann-La Roche Inc., Kingsland Street 340, Nutley, 07110, New Jersey, USA

    David Fry

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Wilson, C.G.M., Arkin, M.R. (2010). Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied. In: Vassilev, L., Fry, D. (eds) Small-Molecule Inhibitors of Protein-Protein Interactions. Current Topics in Microbiology and Immunology, vol 348. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_93

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