Oral immunoproteasome inhibitor ent-F10 potently and selectively suppresses inflammation in mouse ulcerative colitis and rat rheumatoid arthritis models

The immunoproteasome plays a critical role in antigen presentation, inflammatory responses, and T-cell differentiation. Its overexpression can lead to the abnormal generation of self-antigen peptides, promoting their presentation on MHC class I molecules, which breaks immune tolerance and activates CD8+ T cells, driving autoimmune pathological processes. While immunoproteasome inhibitors are promising therapeutic targets for autoimmune diseases like rheumatoid arthritis and ulcerative colitis, existing inhibitors often suffer from poor selectivity and limited oral bioavailability, hindering their clinical development. This gap necessitates the discovery of novel compounds with improved pharmacological profiles.

Researchers designed and screened a series of novel compounds to identify an orally active immunoproteasome inhibitor. The lead compound, ent-F10, was characterized for its inhibitory activity and selectivity against the β5i subunit. Its oral in vivo pharmacodynamics were evaluated in a mouse model of ulcerative colitis. Furthermore, the compound's oral efficacy was assessed in a rat model of rheumatoid arthritis to determine its dose-dependent effects. Safety profiling included evaluating its inhibitory activity against hERG channels to assess potential cardiac toxicity risks.

Compound ent-F10 demonstrated potent and highly selective inhibition against the β5i subunit of the immunoproteasome, with an IC50 of 0.08 μM. This selectivity was further highlighted by a β5/β5i selectivity ratio of 123.8, indicating a strong preference for the immunoproteasome's specific catalytic subunit over the constitutive proteasome. In the mouse ulcerative colitis model, ent-F10 exhibited favorable oral in vivo pharmacodynamics, suggesting effective systemic exposure and target engagement after oral administration. Moreover, the compound showed dose-dependent oral efficacy in a rat model of rheumatoid arthritis, indicating its potential to mitigate disease progression in a therapeutically relevant manner. Importantly, ent-F10 exhibited lower inhibitory activity against hERG channels, reducing the potential risk of cardiac toxicity. This safety profile is a significant advantage for a potential therapeutic agent. The combination of potency, selectivity, oral bioavailability, and reduced cardiac risk positions ent-F10 as a promising drug candidate. This comprehensive profile addresses key limitations of previous immunoproteasome inhibitors.

ent-F10 achieved potent β5i inhibition with an IC50 of 0.08 μM and a remarkable β5/β5i selectivity ratio of 123.8, alongside dose-dependent oral efficacy in two distinct animal models of autoimmune disease.