RORγt inhibitors in clinical development for the treatment of autoimmune diseases: challenges and opportunities

Nuclear receptor retinoid-related orphan receptor gamma-t (RORγt) is a major transcription factor for Th17 cell differentiation and IL-17 production. RORγt has been considered as a promising drug target for the treatment of IL-17-mediated inflammatory diseases. Numerous small molecule inhibitors have been discovered, and more than twenty of RORγt inhibitors have been advanced to clinical trials. However, none of these compounds has yet achieved market approval. This manuscript summarizes the development of 22 clinical-stage RORγt inhibitors, including their structures, patent applications, and clinical trial status, based on publications and patents available up to November 2024. The discovery of RORγt inhibitors was considered as an exciting field for the development of small molecular treatments, which has gone through a boom period in the past ten years. However, some of the leading RORγt inhibitors recently failed in clinical trials due to lack of efficacy or having some safety concerns, although a few of small molecule candidates targeting RORγt are still in trials and more in preclinical studies. Realizing the challenge, researchers started to develop different approaches such as dual targeting or exploring new indications, utilizing the potential value of RORγt inhibitors.