Discovery of an oral, potent and highly selective immunoproteasome inhibitor for the treatment of rheumatoid arthritis and ulcerative colitis.

The immunoproteasome plays a critical role in enhancing antigen presentation, regulating inflammatory responses and modulating T-cell differentiation. Its overexpression can lead to abnormal generation of self-antigen peptides and promote their presentation on MHC class I molecules, thereby breaking immune tolerance, activating CD8+ T cells and driving autoimmune pathological processes. Therefore, as a promising therapeutic target for autoimmune diseases, a variety of immunoproteasome inhibitors have been developed. However, these inhibitors have limitations in terms of selectivity and oral bioavailability, which restricts their development in clinical applications. To address these, we designed a series of novel compounds and then screened compound ent-F10, which is an orally active immunoproteasome inhibitor. Compound ent-F10 exhibits potent and highly selective inhibition against the β5i subunit (IC50: 0.08 μM), with a β5/β5i selectivity ratio of 123.8. In the mouse ulcerative colitis model, ent-F10 demonstrates favorable oral in vivo pharmacodynamics. Furthermore, ent-F10 also showed dose-dependent oral efficacy in a rat rheumatoid arthritis model. Moreover, ent-F10 exhibits lower inhibitory activity against hERG, reducing the potential risk of cardiac toxicity, which further demonstrates its safety. Collectively, ent-F10 can be developed as a potent, selective and orally available drug candidate.