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Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors

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Nuclear Receptors in Human Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1390))

Abstract

This chapter focuses on the development of drugs targeting the N-terminal domain of nuclear hormone receptors, using progress with the androgen receptor as an example. Historically, development of therapies targeting nuclear hormone receptors has focused on the folded C-terminal ligand-binding domain. Therapies were traditionally not developed to target the intrinsically disordered N-terminal domain as it was considered “undruggable”. Recent developments have now shown it is possible to direct therapies to the N-terminal domain. This chapter will provide an introduction of the structure and function of the domains of nuclear hormone receptors, followed by a discussion of the rationale supporting the development of N-terminal domain inhibitors. Chemistry and mechanisms of action of small molecule inhibitors will be described with emphasis on N-terminal domain inhibitors developed to the androgen receptor including those in clinical trials.

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Authors and Affiliations

  1. Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer, Vancouver, BC, Canada

    Marianne D. Sadar

  2. Department of Pathology and Laboratory Science, University of British Columbia, Vancouver, BC, Canada

    Marianne D. Sadar

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Editors and Affiliations

  1. College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Moray J. Campbell

  2. Department of Surgery & Cancer, Imperial College London, London, UK

    Charlotte L. Bevan

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Sadar, M.D. (2022). Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors. In: Campbell, M.J., Bevan, C.L. (eds) Nuclear Receptors in Human Health and Disease. Advances in Experimental Medicine and Biology, vol 1390. Springer, Cham. https://doi.org/10.1007/978-3-031-11836-4_18

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