Nuclear receptors (NRs) are a superfamily of intracellular ligand-modulated transcription factors. These factors regulate various physiological processes such as reproduction, cell growth, differentiation, metabolism, and homeostasis (Frigo et al., 2021). The superfamily consists of 48 members in humans, each sharing a conserved structural and functional organization. They are categorized into four subfamilies based on their DNA binding property and the mode of dimerization: (i) Group I receptors form homodimers and include steroid hormone receptors that bind to DNA half-sites arranged as inverted repeats, (ii) Group II receptors form heterodimers with Retinoid X Receptor (RXR) and bind to direct repeats present within the response elements of target genes, (iii) Group III receptors and (iv) Group IV receptors include dimeric and monomeric orphan receptors respectively. NRs are responsive to a wide range of lipophilic molecules, including steroids, exogenous and endogenous substances, or metabolites. These receptors have a profound effect not only on normal physiology but also on various pathophysiological conditions such as cancer, metabolic disease conditions, and inflammatory diseases (Dash and Tyagi, 2016).

NRs play a central role in signal transduction and possess the unique ability to be activated or inhibited by small molecule modulators interacting with their ligand binding domain. This property makes NRs highly attractive targets for drug development, with about 15 % of the currently marketed drugs targeting these receptors (Overington et al., 2006). Several severe diseases have been effectively treated by modulating the NR functions with small molecules. For instance, the glucocorticoid receptor is targeted by dexamethasone and prednisolone for anti-inflammatory conditions; the estrogen receptor is targeted by tamoxifen for the treatment of breast cancer; the peroxisome proliferator-activated receptors (PPARs), such as PPARγ, are targeted (e.g., Rosiglitazone) for the treatment of type 2 diabetes (Burris et al., 2013; Kojetin and Burris, 2013). Thus, small molecules that interact directly with these transcriptional factors and influence the associated cellular machinery have enormous therapeutic potential.

Steroid hormones, such as androgen and estrogen, are primary sex hormones in males and females and bind to members of the steroid nuclear receptor subfamily (NR3). They drive a wide range of physiological processes, such as sexual maturation and reproduction. Steroid hormone receptors are modular in their structure and composed of the following domains: (i) a poorly conserved and variable N-terminal domain (NTD) (also called Region A/B), (ii) a highly conserved DNA binding domain (DBD) containing two zinc motifs (Region C), (iii) a flexible hinge domain (Region D), (iv) a slightly conserved ligand binding domain (LBD) (Region E), and (v) a least conserved F-region. This subfamily includes estrogen receptors (ER, NR3A1 & NR3A2), glucocorticoid receptor (GR, NR3C1), mineralocorticoid receptor (NR3C2), progesterone receptor (NR3C3) and androgen receptor (AR, NR3C4) (De Bosscher et al., 2020).

The dysregulation of several metabolic pathways including ER and AR-mediated signaling is a hallmark of endocrine-related cancer (Blundon and Dasgupta, 2019). In addition, altered metabolic signaling affects the transcription cascade of these receptors, leading to subsequent cancer development and metastatic progression (Coller, 2014). According to the GLOBOCAN report (2022), the incidence of endocrine-related cancers such as breast cancer and prostate cancer (11.6 % and 7.3 % of all cancers globally, respectively) has been rising over the years, with mortality rates of 6.9 % and 4.1 % respectively (Bray et al., 2024). Current therapeutic regimens aim to target the dysregulated signaling pathways (caused due to receptor overexpression, gene mutations, ligand-independent activations, formation of splice variants, etc.); however, drug resistance has remained a matter of concern for decades. Recent drug discovery approaches including steroidal and non-steroidal molecules focus on developing Selective ER and AR Modulators and Degraders (SERM/Ds & SARM/Ds) that can selectively modulate or downregulate receptor effectiveness, respectively. Recently, a novel approach to regulate the target protein expression in cells has been developed, involving the selective degradation of target proteins by recruiting ubiquitin/proteasomal degradation machinery. This less explored approach involves the binding of E3 ligase to ‘PROteolysis TArgeting Chimeras’ (PROTACs), which consists of peptide ligands that are specific and selective to the target protein (Békés et al., 2022; Han and Sun, 2022).

This review primarily focuses on selective small molecule modulators and PROTAC molecules as best-suited therapeutics for targeting NRs in receptor-associated diseased conditions with a primary focus on ER and AR. First, we briefly discuss traditional modulators and degraders used for targeting cancers. Then, we continue with the recent therapeutic advances for the targeted degradation of ER and AR and explore the prospective use of small molecules for chemical biology research and therapeutic applications.