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

This chapter focuses on the development of drugsDrugs targeting the N-terminal domain of nuclear hormone receptors, using progress with the androgen receptorAndrogen receptors as an example. Historically, development of therapiesTherapies targeting nuclear hormone receptors has focused on the folded C-terminal ligand-binding domain. TherapiesTherapies 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 therapiesTherapies 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 inhibitorsSmall molecule inhibitors will be described with emphasis on N-terminal domain inhibitors developed to the androgen receptorAndrogen receptors including those in clinical trials.