Discovery of Orally Available Prodrugs of Itaconate and Derivatives

Researchers have developed orally available itaconate derivatives to improve the therapeutic potential of itaconate, an endogenous immunomodulator with poor cellular permeability. They synthesized four sets of prodrugs using different pro-moieties, with POC-based prodrugs (P2, P9, P13) showing the most promise in terms of stability, permeability, and pharmacokinetics. Notably, P2 and P13 effectively inhibited inflammatory cytokines in human epidermal keratinocytes and demonstrated favorable pharmacokinetics in oral studies. These findings suggest that prodrug strategies can enhance itaconate's cellular permeability and oral bioavailability, offering potential for clinical applications in systemic and skin disorders.