Cytokines employ JAK kinases for cellular signalling, and deregulation of this pathway is directly linked to human diseases. Several JAK inhibitors have been developed for haematological and inflammatory indications that relieve clinical symptoms but are not curative and show side-effects. Better JAK inhibitors are need but their development requires atom-level understanding of JAK regulation. Our goal is determine how JAK kinases are activated in cytokine receptors and use this information for development of better drugs. We take a systematic multidisciplinary approach using imaging, structural biology methods and AI-guided molecular simulations to obtain a comprehensive understanding of JAK activation. The pseudokinase domain in JAKs has a critical regulatory function and we have shown it to be a valid drug target. The gained molecular understanding on JAK regulation is used in development of more selective inhibitors focusing on the pseudokinase domain.

2024

2028