ROR Family: Promising Drug Targets for Cancer and Inflammatory Diseases

To identify disease-related targets of CSL, we have listed the top 10 CSL target proteins in Table 1. Based on docking and the drug target database, we have screened the ROR family as having the highest affinity. The gscore of RORα, RORβ and RORγ were -9.902, -10.755 and -9.569, respectively. Although their homology is about 68%, their 3D structures are very similar, comprising 9-11 alpha-helices, stem loops, and beta-sheets, and forming a hydrophobic-LBD in the domain [33]. Their functional identity and selectivity for the recognition of the same small-molecule compound need to be explored further [34].

RORs have three subfamily members - RORα, RORβ, and RORγ - that are widely distributed throughout the tissues of the organism, with most isoforms being able to enter the nucleus to regulate the transcription of target genes. They exhibit different tissue specificities and participate in different physiological processes. RORα is widely expressed in many tissues, including cerebellar Purkinje cells, liver, thymus, skeletal muscle, skin, lung, adipose tissue, and kidney. RORγ has a similar broad expression pattern, but very high levels are observed in the thymus. RORβ is found in areas of the central nervous system involved in sensory information processing, such as the retina and pineal gland [35].

RORs have a key regulatory role in cancer and in a variety of autoimmune diseases and inflammatory responses. RORα and RORγ are important regulators of multiple immune functions and are closely associated with the regulation of multiple autoimmune and inflammation-related diseases. RORγ is a key factor in the differentiation and development of Th17 cells and targeting RORγ inhibition is an important direction for the treatment of inflammatory responses. In contrast, studying agonists of RORα is an important idea for the treatment of inflammatory diseases. RORα is also involved in the development of many malignant tumors, including liver cancer, breast cancer, glioma, and colorectal cancer. Restoring RORα expression levels inhibits the proliferation, migration, and invasion of tumor cells, making it a potential target for anti-tumor therapy [36-38].