Nuclear Receptors
Jon K Obst, Amy H Tien, Marianne D Sadar

Steroid hormone receptors are ligand-activated transcription factors, acting as master regulators of gene expression. Steroid receptors mediate formation of large protein complexes by recruiting coregulatory proteins and transcriptional machinery to specific genomic regions. Unlike the structured ligand-binding or DNA-binding domains, the N-terminal domain (NTD), where many of these protein-protein interactions occur, contains extended regions of intrinsic disorder. Interactions in the NTD and allosteric binding elsewhere induce temporary and reversible changes in the NTD structure, substantially influencing the repertoire of potential binding partners. This structural plasticity is key for the steroid receptors to coordinate intra- and intercellular signals into a tissue specific response. Designing small molecule inhibitors against intrinsically disordered proteins (IDP) in general has proven difficult as structural information is limited. While some progress has been made in this area, only recently has any molecule targeting IDPs progressed beyond the preclinical stage. Here we summarize the discovery and development of sintokamides, niphatenones, and EPI compounds which target the intrinsically disordered NTD of the androgen receptor. These are the first drugs to target the NTD of any steroid receptor, and EPI-506 and EPI-7386 remain the only compounds that bind to an IDP to have been tested in clinical trials.

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