Selective steroid receptor modulators, degraders and PROTACs: Therapeutic strategies in management of endocrine-related cancers

Endocrine-related disorders are highly prevalent globally, affecting millions of people. Such diseases are multifactorial in origin and are influenced by the complex interplay of genetics, lifestyle, and environmental factors. Recurring disruptions in the endocrine homeostasis can lead to a cascade of endocrine-related cancers. It is well known that nuclear receptors (NRs), particularly estrogen receptor and androgen receptor malfunctioning promote the oncogenesis of breast cancer and prostate cancer, respectively. However, existing therapeutics against these diseases, including aromatase inhibitors, (anti-) hormonal therapy, etc., often yield limited success, prompting to explore alternative methods of disease management. Additionally, drug resistance is prominent in cancer patients undergoing multidrug therapy. Currently, novel drug design strategies targeting NRs are being implemented for the discovery of a new generation of small molecule modulators, including selective NR modulators (SNuRMs) and degraders (SNuRDs). Moreover, proteolysis-targeting chimeras (PROTACs) as NR degraders, are also being developed primarily to overcome drug resistance, enhance protein selectivity, and mitigate off-target toxicity. This review highlights recent advancements in SNuRMs and SNuRDs for managing NRs-associated endocrine/metabolic disorders. Furthermore, we discuss the therapeutic potential of PROTAC degraders as a stand-alone strategy for receptor-mediated disease intervention, offering new avenues for precision medicine.