Discovery of selective JAK1/2 inhibitor H018, a phase II agent with demonstrated preclinical anti-rheumatoid...

Janus kinase (JAK) inhibitors represent a class of oral therapeutics for rheumatoid arthritis (RA), demonstrating superior clinical efficacy compared to conventional disease-modifying antirheumatic drugs (DMARDs). However, pan-JAK inhibitors are associated with side effects such as infections and hematologic toxicity, and selective JAK inhibitors exhibit diminished efficacy. Guided by the dual mechanism of JAK1 selectivity driving efficacy and JAK2 inhibition to enhance anti-inflammatory effects, we employed rational drug design to develop the highly selective JAK1/2 inhibitor H018 (RAI-20), intending to improve the drug safety while simultaneously managing adverse effects within a reasonable range. Compound RAI-20 exhibited significantly optimized targeting properties, with kinase inhibitory activity and isoform subtype selectivity comprehensively surpassing clinically approved JAK1 inhibitor Filgotinib, thereby establishing a novel strategic strategy for JAK1/2 inhibitor design. Notably, compound RAI-20 demonstrated distinct advantages in key pharmacokinetic and safety assessment parameters, including enhanced plasma stability, significantly improved systemic exposure (AUC) and prolonged duration of half-life. Furthermore, RAI-20 elicited potent, dose-dependent protection against RA in the collagen-induced arthritis (CIA) model, and its efficacy exceeds some marketed JAK inhibitors. Currently, compound RAI-20 has progressed to Phase II clinical trials and is poised to be a potential RA treatment option that combines high efficacy with low toxicity.