Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases

•  Introduction ‐  Jaks in disease ‐  Jak2‐V617F signal transduction •  Structure/function: the potential interest of the Jak domains as drug targets ‐  The FERM domain ‐  The FERM domain as drug target ‐  The SH2 domain ‐  The SH2 domain as drug target ‐  The pseudokinase domain ‐  The pseudokinase domain as drug target ‐  The kinase domain ‐  The kinase domain as drug target ‐  Summary •  The growing family of ATP‐competitive nanomolar Jak inhibitors •  Analogue‐sensitive kinases and possible applications to Jaks ‐  Chemical genetics to characterize kinases ‐  Chemical genetics in practice: possible pitfalls and requirements ‐  Advantages and possible applications of the chemical genetics approach ‐  Investigation of specific kinase‐mediated effects ‐  Specific and flexible pharmacologic intervention allows target validation of compounds from drug screens ‐  Identification of direct substrates •  Structure‐based interpretation of the Jak mutations ‐  Mutations within the FERM and SH2 domains ‐  Mutations within the kinase‐like domain ‐  Mutations within the kinase domain •  Perspectives