Article (Scientific journals)
Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases.
Haan, Claude; Behrmann, Iris; Haan, Serge
2010In Journal of Cellular and Molecular Medicine, 14 (3), p. 504-27
Peer reviewed
 

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Keywords :
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
Abstract :
[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Haan, Claude ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Behrmann, Iris ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Haan, Serge ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Language :
English
Title :
Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases.
Publication date :
2010
Journal title :
Journal of Cellular and Molecular Medicine
ISSN :
1582-1838
Volume :
14
Issue :
3
Pages :
504-27
Peer reviewed :
Peer reviewed
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