Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges

Rokosz, Laura L.; Beasley, James R.; Carroll, Carolyn DiIanni; Lin, Tsung H.; Zhao, Jinwen; Appell, Kenneth C.; Webb, Maria L.

doi:10.1517/14728222.12.7.883

Cited by 47 publications

(32 citation statements)

References 114 publications

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“…Because phosphorylation events in a cell are critical for inter- and intracellular communication, and because these signaling networks are often deregulated in disease states, much effort has gone into developing kinase inhibitors in the hopes of treating diseases such as cancer and autoimmune and inflammatory disorders (26). Unfortunately, the high structural conservation among kinases has posed a challenge in generating an inhibitor that is specific for a particular kinase (5).…”

Section: Discussionmentioning

confidence: 99%

Generation of a Novel System for Studying Spleen Tyrosine Kinase Function in Macrophages and B Cells

Miller¹,

Zhang

Shokat

et al. 2009

The Journal of Immunology

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Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is expressed primarily in hematopoietic cells. Because this protein has been implicated in processes such as Fc-mediated phagocytosis, BCR signaling, oxidative burst, degranulation, cytokine secretion, and integrin-mediated outside-in signaling, it is hypothesized that Syk may be a viable target in the treatment of a variety of autoimmune and inflammatory diseases. Because efforts to design a small-molecule therapeutic that specifically inhibits Syk have been largely unsuccessful, and genetic studies of Syk have been hampered by the fact that syk−/− mice die in utero, we have taken a chemical genetic approach to study the function of Syk. Specifically, we have created a mutant form of Syk that retains its wild-type function, but is susceptible to inhibition by enlarged derivatives of the tyrosine kinase inhibitor, PP1. We report in this study that Syk M442A S505A reconstituted wild-type function when introduced into murine syk−/− bone marrow-derived macrophages and syk−/− DT40 chicken B cells, as determined by functional and biochemical assays. Furthermore, after screening a series of PP1 derivatives, we identified one compound, namely 2,3-DMB-PP1, that specifically inhibited Syk M442A S505A, but not wild-type Syk. This system provides us with the power to characterize immune functions that are Syk specific, and furthermore, it provides us with a tool to assess how inhibition of Syk may alter an immune response and influence disease pathogenesis and/or progression.

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Section: Discussionmentioning

confidence: 99%

Generation of a Novel System for Studying Spleen Tyrosine Kinase Function in Macrophages and B Cells

Miller¹,

Zhang

Shokat

et al. 2009

The Journal of Immunology

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“…It is expressed primarily in B cells, mast cells, platelets, and myeloid cells 76. Mutations in the BTK gene result in X-linked aggamaglobulinaemia (XLA), a disease characterized by marked reduction in numbers of mature B cells and by severe immunodeficiency.…”

Section: Tyrosine Kinases: the Frontrunnersmentioning

confidence: 99%

“…BTK transduces BCR signaling in B cells, FcεR1 signaling in mast cells, and toll-like receptor (TLR) signaling in monocytes. Monocytes from XLA patients exhibit defective TNF production in response to TLR stimulation, while BTK-deficient mast cells exhibit impairment of degranulation, histamine release, and cytokine production 76. A relatively selective BTK inhibitor, compound 4 was shown to be efficacious in an LPS-induced mouse model of RA—but its therapeutic use may be limited because it is an irreversible inhibitor 70,76.…”

Section: Tyrosine Kinases: the Frontrunnersmentioning

confidence: 99%

A Multitude of Kinases—Which are the Best Targets in Treating Rheumatoid Arthritis?

Lindström

Robinson

2010

Rheumatic Disease Clinics of North America

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Synopsis Small-molecule kinase inhibitors are increasingly taking center stage in the quest for new drugs for the treatment of rheumatoid arthritis (RA). By targeting kinases, many of which orchestrate multiple signaling pathways, small-molecule inhibitors can exert potent anti-inflammatory and immunomodulatory effects. The success of small-molecule kinase inhibitors in the treatment of cancer, coupled with greater insight into inflammatory and immune signaling, has spurred efforts to identify kinases that could be targeted for the treatment of chronic inflammatory disorders such as RA. Several kinases have been convincingly implicated in the pathogenesis of RA, and many kinase inhibitors have proven efficacious in the treatment of inflammatory arthritis in animals; but few kinase inhibitors have so far been tested in RA clinical trials. Here we discuss the challenges and progress in the pursuit of small-molecule kinase inhibitors for RA, including the lessons learnt from the failure of erstwhile front-runner inhibitors and the tentative promise of inhibitors making their debut on the RA stage.

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“…One criterion for our program was to achieve selectivity over JAK2 to minimize adverse hematopoietic effects such as anemia, because JAK2 plays a critical role in erythropoietin and thrombopoietin signaling. 6 We initially targeted selective JAK3 inhibitors based on the considerations that JAK3 defects in human result in severe combined immune deficient (SCID) phenotype and JAK3 is mainly expressed in hematopoietic cells 7 (other JAK members more widely expressed). However, because of their unique roles in the cytokine signaling process, we were also interested in compounds that inhibit both JAK3 and JAK1 or JAK3 and TYK2 to assess the optimal selectivity profile for achieving maximal efficacy while limiting potential side effects.…”

mentioning

confidence: 99%

“…Reaction of diethyl ethoxymethylenemalonate(6) with N-aminopyrrole at elevated temperature proceeded to give malonate 7. Upon heating to 220 o C using Dowtherm TM as heat transfer fluid, compound 7 underwent intramolecular Friedel-Crafts cyclization to yield the pyrrolo[1,2-b]pyridazine core 8.…”

mentioning

confidence: 99%

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors

Duan

Jiang

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges

Cited by 47 publications

References 114 publications

Generation of a Novel System for Studying Spleen Tyrosine Kinase Function in Macrophages and B Cells

Generation of a Novel System for Studying Spleen Tyrosine Kinase Function in Macrophages and B Cells

A Multitude of Kinases—Which are the Best Targets in Treating Rheumatoid Arthritis?

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors

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