Pharmacological targeting of the JAK–STAT pathway: new concepts and emerging indications

Abstract

Type I/II cytokine receptors mediate cytokine-specific biological responses by employing a defined combination of four Janus kinases (JAKs) and seven signal transducers and activators of transcription (STATs) for cellular signal transduction. Deregulation of the JAK–STAT pathway leads to various diseases, with JAK and STAT proteins representing attractive therapeutic targets. Fifteen JAK inhibitors are approved for several immunological and haematological diseases, offering significant benefits for patients. However, safety restrictions have limited their clinical use. Mechanistic and structural insights are driving current drug development approaches focused on improving their potency, selectivity and safety. Development of STAT inhibitors has been more challenging, and none has yet received clinical approval, although promising new compounds are now entering clinical trials. This Review discusses the recent advances in JAK and STAT inhibitor development and presents emerging therapeutic indications for JAK–STAT inhibition.