Targeting Nuclear Receptors with PROTAC degraders

Nuclear receptors comprise a class of intracellular transcription factors whose major role is to act as sensors of various stimuli and to convert the external signal into a transcriptional output. Nuclear receptors (NRs) achieve this by possessing a ligand binding domain, which can bind cell permeable agonists, a DNA-binding domain, which binds the upstream sequences of target genes, and a regulatory domain that recruits the transcriptional machinery. The ligand binding alters the activation state of the NR, either by activating or inactivating its transcriptional output. Given the central role of NRs in signal transduction, many currently approved therapeutics modulate the activity of NRs. Here we discuss how PROTAC degraders afford a novel approach to abrogate the downstream signaling activity of NRs. We highlight six broad functional reasons why PROTAC degraders are preferable to the classical ligand binding pocket antagonists, with specific examples provided for each category. Lastly, as Androgen Receptor and Estrogen Receptor PROTAC degraders are being pursued as treatment for prostate cancer and breast cancer, respectively, a rationale is provided for the translational utility for the degradation of these two NRs. •Targeting Nuclear Receptors (NRs) with PROTACs is agonism agnostic.•PROTACs are less susceptible to competing endogenous ligands.•PROTACs target constitutive and non-agonist based activation of NRs.•Degradation overcomes feedback upregulation of the drug target.•Degradation can enable the targeting of orphan receptors.