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

Journal of Cellular and Molecular Medicine
Claude HaanSerge Haan

Abstract

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.

Citations

Jul 24, 2012·Nature Structural & Molecular Biology·Rajintha M BandaranayakeStevan R Hubbard
Mar 3, 2012·Cold Spring Harbor Perspectives in Biology·Douglas A Harrison
Jun 23, 2012·PloS One·Michaela Prchal-MurphyMathias Müller
Mar 12, 2011·Haematologica·Tekla HornakovaJean-Christophe Renauld
Sep 10, 2013·Nature Structural & Molecular Biology·Angela V TomsMichael J Eck
Jan 11, 2013·Journal of Cellular and Molecular Medicine·Karoline GäblerClaude Haan
Dec 6, 2011·European Journal of Cell Biology·René EulenfeldFred Schaper
May 16, 2012·Molecular and Cellular Biochemistry·Kavitha GnanasambandanPeter P Sayeski
Dec 19, 2018·Frontiers in Oncology·Juuli RaivolaOlli Silvennoinen
Apr 1, 2019·Inflammopharmacology·Anja DulliusMárcia Inês Goettert
Jan 2, 2020·Cancers·Juuli RaivolaOlli Silvennoinen
Jun 20, 2017·ACS Medicinal Chemistry Letters·Ana S NewtonWilliam L Jorgensen

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