Selective Targeting of JAK1/TYK2: The Therapeutic Potential of TLL018 in Autoimmune Conditions

Janus kinases (JAKs) play a crucial role in cellular responses to proinflammatory cytokines and are targets for treating autoimmune diseases. However, existing JAK inhibitors have limitations due to their lack of selectivity, leading to adverse effects. The pursuit is to develop a JAK1/TYK2 inhibitor that avoids targeting JAK2 and JAK3, potentially offering a better therapeutic profile.

The objective of this study was to discover a highly selective JAK1/TYK2 inhibitor, TLL018, with the potential to treat autoimmune diseases like rheumatoid arthritis (RA). The compound was designed using predictive structure-activity relationships to achieve selectivity for JAK1 and TYK2 while sparing JAK2, JAK3, and other kinases. Its activity was evaluated through a series of enzyme, cell, and whole blood assays, as well as in vivo arthritis models.

TLL018 proved to be a potent and selective JAK1/TYK2 inhibitor, showing high oral bioavailability and selectivity against JAK1 and TYK2 in vitro. It demonstrated significant cellular activity in JAK1-mediated IL-6 signaling with a high degree of selectivity. In rat and mouse arthritis models, TLL018 exhibited dose-dependent efficacy, significantly reducing inflammation and disease markers without substantial inhibition of JAK2 and JAK3.

Supporting its clinical development, TLL018 showed excellent absorption, distribution, metabolism, excretion, and pharmacokinetic properties, along with a clean safety profile in preclinical studies. The compound's preclinical pharmacology, pharmacokinetics, and toxicology data indicate a promising pharmaceutical profile, suggesting its potential in treating RA and other autoimmune diseases. Clinical trials for TLL018 are currently underway.