Reference : Perspectives for the use of structural information and chemical genetics to develop i...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/16409
Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases.
English
Haan, Claude mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Haan, Serge mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
2010
Journal of Cellular & Molecular Medicine
14
3
504-27
Yes (verified by ORBilu)
International
1582-1838
England
[en] Animals ; Catalytic Domain/genetics ; Drug Discovery ; Enzyme Inhibitors/chemistry/therapeutic use ; Hematologic Diseases/drug therapy/enzymology ; Humans ; Janus Kinases/antagonists & inhibitors/chemistry/genetics ; Mutation ; Protein Structure, Tertiary ; src Homology Domains/genetics
[en] Gain-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.
http://hdl.handle.net/10993/16409

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