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•  PerspectivesGain‐of‐function mutations in the genes encoding Janus kinases have been discovered in various haematologic diseases. Jaks are composed of a FERM domain, an SH2 domain, a pseudokinase domain and a kinase domain, and a complex interplay of the Jak domains is involved in regulation of catalytic activity and association to cytokine receptors. Most activating mutations are found in the pseudokinase domain. Here we present recently discovered mutations in the context of our structural models of the respective domains. We describe two structural hotspots in the pseudokinase domain of Jak2 that seem to be associated either to myeloproliferation or to lymphoblastic leukaemia, pointing at the involvement of distinct signalling complexes in these disease settings. The different domains of Jaks are discussed as potential drug targets. We present currently available inhibitors targeting Jaks and indicate structural differences in the kinase domains of the different Jaks that may be exploited in the development of specific inhibitors. Moreover, we discuss recent chemical genetic approaches which can be applied to Jaks to better understand the role of these kinases in their biological settings and as drug targets.