Selective JAK Inhibitors

Dymock, Brian; Yang, Eugene Guorong; Chu-Farseeva, Yu-yi; Yao, Lianbin

doi:10.4155/fmc.14.92

Cited by 36 publications

(46 citation statements)

References 99 publications

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“…There are currently a little over 10 JAK selective inhibitors in clinical trials, however few are specific only for JAK2 with the exception of gandotinib and BMS-911543. Only ruxolitinib (selective inhibitor of JAK1 and JAK2) has received Food and Drug Administration (FDA) approval for the treatment of myelofibrosis, while many other compounds have been discontinued due to toxicity [ 80 , 82 ]. Ruxolitinib does improve constitutional symptoms and splenomegaly, but does not substantially reduce mutant allele burden in patients and these benefits come at the cost of frequent anaemia and thrombocytopenia [ 83 , 84 ].…”

Section: The Mechanism Of Jak2 Activationmentioning

confidence: 99%

“…Clinical trials of polycythemia vera and essential thrombocythemia patients with lestaurtinib, a multikinase inhibitor of JAK1, JAK2, JAK3, FLT3 and TRKA/B/C has shown to modestly reduce JAK2-V617F allele burden and spleen size [ 80 , 87 ]. Tofacitinib (tasocitinib), a pan-JAK inhibitor has been FDA approved for rheumatoid arthritis and is being studied for the treatment of a range of disorders including polycythemia vera, psoriasis, ankylosing spondylitis and for the prevention of transplant rejection [ 82 , 88 , 89 ]. Further improvements to the mechanisms of JAK2 inhibition and increased specificity should lead to more effective therapeutic outcomes.…”

Section: The Mechanism Of Jak2 Activationmentioning

confidence: 99%

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JAK2 activation by growth hormone and other cytokines

Waters

Brooks

2015

Biochemical Journal

115

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Growth hormone (GH) and structurally related cytokines regulate a great number of physiological and pathological processes. They do this by coupling their single transmembrane domain (TMD) receptors to cytoplasmic tyrosine kinases, either as homodimers or heterodimers. Recent studies have revealed that many of these receptors exist as constitutive dimers rather than being dimerized as a consequence of ligand binding, which has necessitated a new paradigm for describing their activation process. In the present study, we describe a model for activation of the tyrosine kinase Janus kinase 2 (JAK2) by the GH receptor homodimer based on biochemical data and molecular dynamics simulations. Binding of the bivalent ligand reorientates and rotates the receptor subunits, resulting in a transition from a form with parallel TMDs to one where the TMDs separate at the point of entry into the cytoplasm. This movement slides the pseudokinase inhibitory domain of one JAK kinase away from the kinase domain of the other JAK within the receptor dimer–JAK complex, allowing the two kinase domains to interact and trans-activate. This results in phosphorylation and activation of STATs and other signalling pathways linked to this receptor which then regulate postnatal growth, metabolism and stem cell activation. We believe that this model will apply to most if not all members of the class I cytokine receptor family, and will be useful in the design of small antagonists and agonists of therapeutic value.

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Section: The Mechanism Of Jak2 Activationmentioning

confidence: 99%

Section: The Mechanism Of Jak2 Activationmentioning

confidence: 99%

JAK2 activation by growth hormone and other cytokines

Waters

Brooks

2015

Biochemical Journal

115

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“…JAK1 and JAK3 have similar effects on cytokine signaling, however, JAK 3 expression is limited to hematopoietic cells. 69 JAK1 is associated with a wider array of receptor chains and with a more widespread effect than JAK3. 70 Tofacitinib and oclacitinib inhibit JAK1/3 and thus prevent upregulation of interleukins involved in lymphocyte stimulation.…”

Section: Discussionmentioning

confidence: 99%

Comparative efficacy of topical oclacitinib 0.1% and tacrolimus 0.01% in canine keratoconjunctivitis sicca

Oliveira

Williams

Bollmann

et al. 2019

Veterinary Ophthalmology

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Objective To assess the efficacy of 0.1% oclacitinib as a single agent, and in combination with tacrolimus 0.01%, for the control of ophthalmic signs of keratoconjunctivitis sicca (KCS) in dogs. Animals studied Thirty‐two dogs (57 eyes) diagnosed with idiopathic KCS were included. Inclusion criteria were Schirmer Tear Test 1 (STT‐1) values <15 mm/min and concurrent clinical signs such as ocular hyperemia and discharge. Procedures The animals were submitted to a randomized, open‐label, 5‐week study and divided into 3 treatment groups treated with the following ophthalmic solutions: (a) 0.1% oclacitinib, (b) 0.1% oclacitinib +0.01% tacrolimus, and (c) 0.01% tacrolimus. Eye drops were instilled twice daily (12‐hour intervals). At each follow‐up examination, STT‐1, clinical signs, and potential drug side effects were assessed. Results Oclacitinib did not significantly improve STT‐1 values or clinical scores. Tacrolimus alone and in combination with oclacitinib increased mean STT‐1 values by 11.84 ± 5.2 and 12.46 ± 5.3 mm/min, respectively (P = 0.0001). Clinical scores of ocular discharge and hyperemia also improved significantly in both groups receiving treatment with tacrolimus (P < 0.05). However, addition of oclacitinib to tacrolimus provided no additional improvement over tacrolimus alone. Conclusions Topical 0.1% oclacitinib twice daily is not effective in controlling the ocular signs of KCS in dogs. 0.01% tacrolimus increased STT‐1 values significantly and could potentially be used as a treatment for mild‐to‐moderate cases of KCS. Synergism between drugs did not occur, and therefore the use of oclacitinib is not justified in cases of canine KCS.

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“…Furthermore, present inhibitors are not specific to somatic JAK mutant proteins, such as JAK1 V658F and JAK2 V617F that are connected to acute lymphoblastic leukemia and polycythemia vera, respectively. Consequently, selective JAK inhibitors (with diverse selectivity profiles) are still very much sought after, not only to provide drug candidates with abolished side effects, but also to (i) enable the better elucidation of the specific functions of the different JAK subtypes especially with somatic mutations, and to (ii) develop novel therapeutics for other inflammatory and autoimmune diseases .…”

Section: Introductionmentioning

confidence: 99%

Identification of 8‐Hydroxyquinoline Derivatives Active Against Somatic V658F Mutant JAK1‐Dependent Cells

Kingsford-Adaboh

Bajusz

Baskin

et al. 2016

Archiv der Pharmazie

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Janus kinases (JAKs) and their gain-of-function mutants have been implicated in a range of oncological, inflammatory, and autoimmune conditions, which has sparked great research interest in the discovery and development of small-molecule JAK inhibitors. Two molecules are currently marketed as JAK inhibitors, but due to the displayed side effects (owing to their suboptimal selectivities among the various JAK subtypes) new JAK inhibitors are still sought after. We present the results of an extensive virtual screening campaign based on a multi-step screening protocol involving ligand docking. The screening yielded five new, experimentally validated inhibitors of JAK1 with 8-hydroxyquinoline as a novel hinge-binding scaffold. The compounds did not only display favorable potencies in a JAK1 -driven cell-based assay but were also shown to be non-cytotoxic on rat liver cells.

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Selective JAK Inhibitors

Cited by 36 publications

References 99 publications

JAK2 activation by growth hormone and other cytokines

JAK2 activation by growth hormone and other cytokines

Comparative efficacy of topical oclacitinib 0.1% and tacrolimus 0.01% in canine keratoconjunctivitis sicca

Identification of 8‐Hydroxyquinoline Derivatives Active Against Somatic V658F Mutant JAK1‐Dependent Cells

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