Bibliografie tematiche / JAK/STAT inhibitors

Letteratura scientifica selezionata sul tema "JAK/STAT inhibitors"

Autore: Grafiati

Pubblicato: 22 giugno 2024

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Articoli di riviste sul tema "JAK/STAT inhibitors":

Jones, Dan, Justin Windham, Brian Stewart, Luis Fayad, Alma Rodriguez e Fredrick B. Hagemeister. "Differential JAK-STAT Pathway Activation in Primary Mediastinal Large B-Cell Lymphoma: Two Subgroups with Differential Cytokine Activation Patterns and Predicted Responses to Kinase Inhibitors." Blood 114, n. 22 (20 novembre 2009): 968. http://dx.doi.org/10.1182/blood.v114.22.968.968.

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Abstract Abstract 968 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a specialized type of diffuse large B-cell lymphoma which shows diagnostic and pathogenetic overlap with mediastinal classical Hodgkin lymphoma. Approximately 60% of patients with PMBCL have good response to conventional chemoradiotherapy with the rest often showing distant relapses. Microarray studies of PMBCL have revealed overexpression of components and targets of the JAK-STAT signaling pathways including upregulation of IL13 receptor and STAT1; a subset of PMBCL have genome amplification of JAK2 or deletion of the JAK suppressor SOCS1. Given this complexity, we examined the most common mechanism and effects of JAK-STAT dysregulation in a series of newly diagnosed and recurrent PMBCL. Methods: Fifty-three biopsies from 23 patients with PMBCL were assessed and correlated with outcome. JAK2 and SOCS1 copy number status were determined by quantitative PCR on genomic DNA. JAK-STAT pathway activation was probed using reverse transcription quantitative (RQ)-PCR for JAK2, JAK3, and a panel of IL-4 and IL-13 transcriptional targets. JAK-STAT activation was assessed in tissue arrays using antisera against phospho-activation epitopes of STAT1, STAT3, STAT5, and STAT6 using immunohistochemistry (IHC). Activation patterns were modeled in the PMBCL cell line Karpas (K)1106P at baseline and following IL-4 and IL-13 stimulation with or without a range of small molecule inhibitors and blocking antibodies. Growth parameters were measured by MTT and protein levels by flow cytometry, Western blot, RQ-PCR and kinase profiling. Results: JAK2 genomic amplification was present in 40% of PMBCL and SOCS1 deletion in 10% as well as in the K1106P line. By phospho-activation IHC, tumors in 20/23 (87%) patients showed STAT activation, mostly due to STAT1 (60.8%) followed by STAT3 (26.1%), with 6 cases showing mixed patterns. In different tumors, localized and uniform STAT activation patterns were seen. Constitutive STAT activation was correlated with high expression of IL-4 transcription targets including CCL17 and IL13RA as well as JAK2 autophosphorylation and inferior outcome (p = .007). Tumors with more localized foci of activation were associated with alternate transcription patterns. In the K1106P cell line, IL-4 but not IL-13 treatment led to inducible STAT1 activation whereas baseline STAT3/6 activation was highly regulated by cytokine exposure. The JAK2 inhibitor JSI124 blocked IL-4 induced STAT1 activation whereas the JAK inhibitors AG-490, NSC7908 and WHI-P154 did not but did block IL-4/IL-13-induced STAT3 activation. The JAK3 inhibitor ZM39923 was most effective in blocking cell growth but did not block STAT1 activation. Conclusions: JAK2-STAT pathway activation characterizes nearly all cases of PMBCL but genetic mechanisms are distinct leading to distinct patterns of STAT1 activation (driven predominantly through the type I IL-4 receptor) and STAT3/6 activation (driven predominantly through the type II IL13RA/IL4RA) with differential effects on growth parameters and gene regulation. The patterns of STAT activation and target gene expression in primary tumors comprising these two groups mirrored the response to small molecule inhibitors following cytokine exposure in vitro in the K1106P line and highlights differences between IL-4 and IL-13 signaling in PMBCL. Profiling of PMBCL biopsies with phosphoactivation IHC for STAT isoforms may be useful to subcategorize cases and select the optimal JAK-STAT pathway inhibitors for adjuvant therapy. Disclosures: No relevant conflicts of interest to declare.

Malemud, Charles J. "The role of the JAK/STAT signal pathway in rheumatoid arthritis". Therapeutic Advances in Musculoskeletal Disease 10, n. 5-6 (19 maggio 2018): 117–27. http://dx.doi.org/10.1177/1759720x18776224.

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Proinflammatory cytokine activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway is a critical event in the pathogenesis and progression of rheumatoid arthritis. Under normal conditions, JAK/STAT signaling reflects the influence of negative regulators of JAK/STAT, exemplified by the suppressor of cytokine signaling and protein inhibitor of activated STAT. However, in rheumatoid arthritis (RA) both of these regulators are dysfunctional. Thus, continuous activation of JAK/STAT signaling in RA synovial joints results in the elevated level of matrix metalloproteinase gene expression, increased frequency of apoptotic chondrocytes and most prominently ‘apoptosis resistance’ in the inflamed synovial tissue. Tofacitinib, a JAK small molecule inhibitor, with selectivity for JAK2/JAK3 was approved by the United States Food and Drug Administration (US FDA) for the therapy of RA. Importantly, tofacitinib has demonstrated significant clinical efficacy for RA in the post-US FDA-approval surveillance period. Of note, the success of tofacitinib has spurred the development of JAK1, JAK2 and other JAK3-selective small molecule inhibitors, some of which have also entered the clinical setting, whereas other JAK inhibitors are currently being evaluated in RA clinical trials.

Cacciapaglia, F., V. Venerito, S. del Vescovo, S. Stano, R. Bizzoca, D. Natuzzi, N. Lacarpia, M. Fornaro e F. Iannone. "AB0070 INHIBITION OF STAT3 IN PBMCs FROM RHEUMATOID ARTHRITIS PATIENTS: CLUES TO UNDERSTAND SELECTIVITY OF JANUS KINASE INHIBITORS". Annals of the Rheumatic Diseases 81, Suppl 1 (23 maggio 2022): 1167.2–1168. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1997.

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BackgroundThe Janus kinase (Jak) - signal transducer and activator of transcription (STAT) pathway has 4 Jak proteins and 7 STAT factors that mediate intracellular downstream of cytokine receptors. Targeted small-molecule therapies with different bond affinity to Jak proteins have been demonstrated effective in rheumatoid arthritis (RA) treatment, but the clinical significance of selective inhibition remains unclear.ObjectivesTo explore the effect of selective inhibition of Jak-STAT pathway in peripheral blood mononuclear cells (PBMC) from RA patients compared to healthy donors (HD).MethodsIn vitro Jak inhibition of the subunit 3 of phosphorylated (p) than activated STAT was measured by flow cytometry in peripheral blood mononuclear cells (PBMC) from RA patients with active disease (DAS28>5.1) naïve to any DMARDs (n.5) and HD (n.5), following recombinant human 0.1 ng/ml IL-6 (Peprotech – NJ, USA) stimulation. After blood separation, PBMC were overnight incubated with IC50 concentrations of selective Jak1-, Jak2-, Jak3- and Tyk2-inhibitors (Biovision Inc. – CA, USA) with or without IL-6 stimulation. Mean fold-increase of pSTAT3 was then compared in presence of different compounds stimulation.ResultsMean pSTAT3 activity after overnight incubation was significantly higher in RA patients compared to HD (37%; 95CI 8.2-56.7 vs 17.9%; 95CI 4.6-21 – p=0.01). After IL-6 stimulation, a 2-fold and a 1.4-fold increase in pSTAT3 levels was observed in PBMC from RA patients and HD, respectively. In unstimulated PBMC from HD Jak-inhibitors didn’t significantly reduced pSTAT3 activity. In CD14+ cells from RA patients, pSTAT3 activity was reduced with no differences between all four selective Jak-inhibitors, while in CD4+ cells only Jak1-inhibition was able to reduce by 40% pSTAT3 activity. After IL-6 stimulation, the co-culture with Jak1- or JaK3- selective inhibitors was able to significantly reduce pSTAT3 levels in CD4+ lymphocytes, by an average of 20%. While in CD14+ monocytes Jak1-, Jak2- and Jak3- selective inhibitors were able to reduce pSTAT3 activity by a mean of 30%. Tyk-2 selective inhibitor did not interfere with STAT3 activation by IL-6 stimulation of PBMC from RA patients and HD.ConclusionJak/STAT3 activity of PBMC from RA patients with active disease may be differently modulated by specific inhibitors. Selectivity of Jak-inhibitors seems more relevant in lymphocytes after IL-6 stimulation. These preliminary findings may explain discrepancies in effectiveness of selective Jak-inhibitors and pave the way for different choices in clinical practice.References[1]Tanaka Y, et al. Nat Rev Rheumatol. 2022 Jan 5:1–13.[2]Traves PG, et al. Ann Rheum Dis. 2021 Jul;80(7):865-875.[3]Choy EH. Rheumatology (Oxford). 2019 Jun 1;58(6):953-962.Disclosure of InterestsNone declared

Cacciapaglia, F., S. Perniola, S. del Vescovo, S. Stano, R. Bizzoca, D. Natuzzi, M. Fornaro e F. Iannone. "AB0134 IN-VITRO STUDY ON THE EFFECT OF SELECTIVE Jak-INHIBITORS ON PBMCs STAT3 PHOSPHORYLATION FROM SYSTEMIC SCLEROSIS PATIENTS". Annals of the Rheumatic Diseases 81, Suppl 1 (23 maggio 2022): 1196.3–1197. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2625.

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BackgroundSystemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by autoimmunity-driven damage and vasculopathy leading to fibrosis of the skin and internal organs (1). The Janus kinase (Jak) - signal transducer and activator of transcription (STAT) pathway has been evidenced markedly activated in SSc patients (2, 3), and its inhibition has been proved in preclinical and clinical trials (4), but no data on Jak selective inhibition are available.ObjectivesTo explore the effect of selective inhibition of Jak/STAT pathway in peripheral blood mononuclear cells (PBMC) from SSc patients.MethodsIn vitro Jak inhibition of the subunit 3 of phosphorylated (p) than activated STAT was measured by flow cytometry in peripheral blood mononuclear cells (PBMC) from SSc patients naïve to any immunosuppressive and/or corticosteroids (n.5). pSTAT3 activity was also assessed after stimulation with recombinant human 0.1 ng/ml IL-6 (Peprotech – NJ, USA). The PBMC were overnight incubated with IC50 concentrations of selective Jak1-, Jak2-, Jak3- and Tyk2-inhibitors (Biovision Inc. – CA, USA). Percentages of pSTAT3 positive cells were compared in presence of different compounds stimulation.ResultsAfter overnight incubation, percentage of pSTAT3 positive cells was significantly higher in CD14pos compared to CD4pos (16.3%; 95CI 10-22 vs 10.7%; 95CI 4--18, – p=0.02). pSTAT3posCD14pos cells were halved only by selective Jak3-inhibitor, while pSTAT3posCD4pos cells were reduced by 36% by selective Jak1-inhibitor. Selective Jak2- or Tyk2-inhibitors did not interfere with STAT3 phosphorylation in PBMC from SSc patients. After IL-6 stimulation, we observed a 2- and a 1.5-fold increase in percentage of pSTAT3posCD4pos and pSTAT3posCD14pos cells, respectively. pSTAT3posCD14pos cells were reduced in the PBMC co-culture with IL-6 and Jak-selective inhibitors, in contrast no effects were found in CD4pos cells. Specifically, selective Jak1- and Jak3-inhibitors reduced pSTAT3posCD14pos cells by an average of 37% and 25%, respectively. No effects were observed after co-culture with IL-6 and selective Jak2- or Tyk2-inhibitors.ConclusionJak/STAT3 pathway of PBMC from SSc patients with active disease may be differently modulated by specific inhibitors. Selectivity of Jak1- and Jak3-inhibitors seems more relevant, especially in CD14pos monocytes after IL-6 stimulation. These preliminary findings highlight some evidence for effectiveness of selective Jak-inhibitors in SSc treatment.References[1]Benfaremo D, et al. Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches. Biomedicines. 2022;10(1):163.[2]Talotta R. The rationale for targeting the JAK/STAT pathway in scleroderma-associated interstitial lung disease. Immunotherapy. 2021;13(3):241-256.[3]Cacciapaglia F, et al. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is highly expressed in CD14+ circulating cells of scleroderma patients. Rheumatology (Oxford). 2020;59(6):1442-1444.[4]Karalilova RV, et al. Tofacitinib in the treatment of skin and musculoskeletal involvement in patients with systemic sclerosis, evaluated by ultrasound. Rheumatol Int. 2021;41(10):1743-1753.Disclosure of InterestsNone declared

Conzelmann, Michael, Elena Rodionova, Michael Hess, Thomas Giese, Anthony D. Ho, Peter Dreger e Thomas Luft. "Complementary JAK/STAT Signalling Is Required for the Pro-Inflammatory Effects of CD40 Ligation: Differential Effects in Human Myeloid and B Cells." Blood 110, n. 11 (16 novembre 2007): 2413. http://dx.doi.org/10.1182/blood.v110.11.2413.2413.

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Abstract CD40L represents a strong endogenous danger signal that induces pro-inflammatory activation of CD40-expressing cells such as dendritic cells (DC), monocytes, and B cells. However, since CD40 activation alone is insufficient to induce pro-inflammatory cytokines such as IL-12p70, we studied whether CD40-mediated pro-inflammatory activity might be dependent on co-signalling pathways involving JAK/STAT. Using quantitative Western blotting, we demonstrate that JAK/STAT signalling is induced by cytokines such as IL-4, GM-CSF and IFNg, whereas CD40 activation mediates NFkB signalling. CD40L-induced IL-12p70 and IL-10 secretion in human DC, monocytes, B cells, and chronic lymphocytic leukemia (CLL) cells was measured upon complementary JAK/STAT activation by IL-4, GM-CSF and IFNg in the presence and absence of specific inhibitors of JAK2, JAK3, and pan-JAK. Whereas IL-12p70 could not be induced by CD40 ligation or by cytokines alone, IL-12p70 secretion and suppression of IL-10 was reproducibly observed after co-stimulation of CD40L with IL-4, GM-CSF, or IFNg. This effect could be completely reversed by pan-JAK inhibition. Persistence of IL-4/GM-CSF/IFNg-mediated JAK/STAT signalling as late as 12 hours following cellular activation via CD40 was required for IL-12p70 secretion as shown by the effects of delayed JAK inhibition. Similarly, persistence between 12 and 24 hours of IL-12p35 and p40 mRNA expression correlated best with the level of IL-12p70 secretion. Specific inhibition of JAK2 and JAK3 further revealed a context-dependent action of the distinct JAK family members: JAK2 showed a strong co-dominant effect in the setting of IL-4-induced JAK/STAT activity. Both, JAK2 and JAK3 were required for IL-12p70 secretion, whereas JAK2 alone was sufficient to modulate IL-10 secretion. However, in the context of IFNg-induced JAK/STAT signalling in DC, neither JAK2 nor JAK3 inhibition had effects on IL-12p70. Here, only inhibition by the pan-JAK inhibitor involving JAK1 abrogated IL-12p70 secretion, indicating that in IFNg-dependent signalling, JAK2 is apparently sub-dominant to JAK1 and had only a small enhancing effect on IL-10. This context dependence markedly differed in myeloid cells and B cells, as normal and malignant (CLL) B cells maintain a co-dominant JAK2 activity in the context of IFNg-induced JAK/STAT-signalling. In conclusion, complementary JAK/STAT signalling is required for the pro-inflammatory effects of CD40 ligation in humans, with different JAK subset predominance in myeloid and B cells. These results may open new ways of lineage-specific interfering with CD40 signals by modulating JAK/STAT activity using tyrosine kinase inhibitors.

Galli Sanchez, Ana Paula, Tatiane Ester Aidar Fernandes e Gustavo Martelli Palomino. "The JAK-STAT Pathway and the JAK Inhibitors". Journal of Clinical Research in Dermatology 7, n. 5 (30 novembre 2020): 1–6. http://dx.doi.org/10.15226/2378-1726/7/5/001128.

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Dozens of cytokines that bind Type I and Type II receptors use the Janus Kinases (JAK) and the Signal Transducer and Activator of Transcription (STAT) proteins pathway for intracellular signaling, orchestrating hematopoiesis, inducing inflammation, and controlling the immune response. Currently, oral JAK inhibitors are being used to treat many inflammatory and myeloproliferative diseases and are also under investigation in several clinical trials for skin diseases. Thus, dermatologists should understand how the JAK-STAT pathway works as well as the mechanism of action of the JAK inhibitors which will certainly become an important part of the dermatologist’s treatment armamentarium in the next few years. Keywords: JAK inhibitors; Janus Kinases; JAK-STAT Pathway List of Abbreviations: AD: Atopic Dermatitis ADP: Adenosine diphosphate Dmards: Disease-Modifying Antirheumatic Drugs JAK: Janus kinase(s) Jaki: Janus kinase Inhibitor(s) PIAS: Protein Inhibitor of Activated STAT P-STAT: Phosphorylated STAT STAT: Signal Transducer and Activator of Transcription TYK2: Tyrosine Kinase 2 Wsxws: Tryptophan-Serine-X-Tryptophan-Serine

Raivola, Juuli, Teemu Haikarainen, Bobin George Abraham e Olli Silvennoinen. "Janus Kinases in Leukemia". Cancers 13, n. 4 (14 febbraio 2021): 800. http://dx.doi.org/10.3390/cancers13040800.

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Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregulation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are activating somatic mutations and less frequently translocations resulting in constitutively active JAK fusion proteins. JAKs have become important therapeutic targets and currently, six JAK inhibitors have been approved by the FDA for the treatment of both autoimmune diseases and hematological malignancies. However, the efficacy of the current drugs is not optimal and the full potential of JAK modulators in leukemia is yet to be harnessed. This review discusses the deregulation of JAK-STAT signaling that underlie the pathogenesis of leukemia, i.e., mutations and other mechanisms causing hyperactive cytokine signaling, as well as JAK inhibitors used in clinic and under clinical development.

Raivola, Juuli, Teemu Haikarainen e Olli Silvennoinen. "Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling". Cancers 12, n. 1 (27 dicembre 2019): 78. http://dx.doi.org/10.3390/cancers12010078.

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The Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway mediates essential biological functions from immune responses to haematopoiesis. Deregulated JAK-STAT signaling causes myeloproliferative neoplasms, leukaemia, and lymphomas, as well as autoimmune diseases. Thereby JAKs have gained significant relevance as therapeutic targets. However, there is still a clinical need for better JAK inhibitors and novel strategies targeting regions outside the conserved kinase domain have gained interest. In-depth knowledge about the molecular details of JAK activation is required. For example, whether the function and regulation between receptors is conserved remains an open question. We used JAK-deficient cell-lines and structure-based mutagenesis to study the function of JAK1 and its pseudokinase domain (JH2) in cytokine signaling pathways that employ JAK1 with different JAK heterodimerization partner. In interleukin-2 (IL-2)-induced STAT5 activation JAK1 was dominant over JAK3 but in interferon-γ (IFNγ) and interferon-α (IFNα) signaling both JAK1 and heteromeric partner JAK2 or TYK2 were both indispensable for STAT1 activation. Moreover, IL-2 signaling was strictly dependent on both JAK1 JH1 and JH2 but in IFNγ signaling JAK1 JH2 rather than kinase activity was required for STAT1 activation. To investigate the regulatory function, we focused on two allosteric regions in JAK1 JH2, the ATP-binding pocket and the αC-helix. Mutating L633 at the αC reduced basal and cytokine induced activation of STAT in both JAK1 wild-type (WT) and constitutively activated mutant backgrounds. Moreover, biochemical characterization and comparison of JH2s let us depict differences in the JH2 ATP-binding and strengthen the hypothesis that de-stabilization of the domain disturbs the regulatory JH1-JH2 interaction. Collectively, our results bring mechanistic understanding about the function of JAK1 in different receptor complexes that likely have relevance for the design of specific JAK modulators.

Bhagwat, Neha, Priya Koppikar, Outi Kilpivaara, Taghi Manshouri, Mazhar Adli, Ann Mullally, Omar Abdel-Wahab et al. "Heterodimeric JAK-STAT Activation As a Mechanism of Persistence to JAK2 Inhibitor Therapy". Blood 118, n. 21 (18 novembre 2011): 122. http://dx.doi.org/10.1182/blood.v118.21.122.122.

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Abstract Abstract 122 Although JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms, JAK2 inhibitor treatment does not significantly reduce or eliminate the MPN clone in most MPN patients. We therefore sought to characterize mechanisms by which MPN cells can persist despite chronic JAK2 inhibition. We performed saturation mutagenesis followed by next-generation sequencing in JAK2 mutant cells exposed to two different JAK2 inhibitors, INCB18424, a dual JAK1/JAK2 inhibitor, and JAK Inhibitor I, a pan-JAK inhibitor. Although we were able to identify candidate resistance alleles, these alleles were present in less than 50% of the total population. These data and the clinical experience with JAK2 inhibitors suggest that the failure of JAK2 inhibitors to reduce disease burden is not due to acquired drug resistance but rather due to persistent growth and signaling in the setting of chronic JAK2 kinase inhibition. We therefore generated JAK2/MPL mutant JAK2-inhibitor persistent (JAKper) cell lines (SET-2, UKE-1, Ba/F3-MPLW515L). JAKper cell lines are able to survive and proliferate in the presence of JAK2 inhibitors including JAK Inhibitor I, INCB18424 and TG101348 without acquiring second-site resistance alleles and are also insensitive to other JAK inhibitors. Signaling studies revealed JAK-STAT signaling was reactivated in persistent cells at concentrations of inhibitor that completely abrogated signaling in naïve cells, and JAK2 phosphorylation was reactivated in JAK inhibitor persistent cells consistent with reactivation of the JAK-STAT pathway in JAKper cells despite inhibitor exposure. We hypothesized that JAK2 may be activated in trans by other JAK kinases, and found an increased association between activated JAK2 and JAK1/TYK2 consistent with activation of JAK2 in trans by other JAK kinases in JAKper cells. We next assessed whether JAK inhibitor persistence was reversible. Withdrawal of JAK2 inhibitors from JAKper cells for 2 weeks led to resensitization such that JAKper resensitized cells were now sensitive to different JAK2 inhibitors regardless of previous exposure. Resensitization was associated with reversal of heterodimerization and loss of transactivation of JAK2 by JAK1 and TYK2. The reversible nature of JAK inhibitor persistence led us to hypothesize epigenetic alterations are responsible for JAK inhibitor insensitivity in JAKper cells; we observed increased expression of JAK2 at the mRNA and protein level in JAK2 inhibitor persistent cells compared to parental as well as resensitized cells. ChIP-PCR analysis of the JAK2 locus revealed a significant increase in H3K4-trimethylation and a reduction in H3K9 trimethylation in persistent cells compared to parental cells consistent with a change to a more active chromatin state at the JAK2 locus and increased JAK2 mRNA expression in persistent cells. We next assessed whether the same phenomenon of JAK2 inhibitor persistence was observed in vivo. In a MPLW515L-mutant murine bone marrow transplant model of primary myelofibrosis, we observed increased JAK2 expression, increased JAK2 phosphorylation and JAK-inhibitor induced association between JAK1 and JAK2 in hematopoietic cells from INCB18424 treated mice. We next extended our findings to samples from patients treated with INCB18424. We identified 5 patients who had a significant clinical response and 5 patients without a significant clinical response as assessed by spleen size and JAK2V617F allele burden responses and measured JAK2 granulocyte mRNA expression before and during INCB18424 treatment. We found that JAK2 mRNA levels significantly increased in INCB18424 nonresponders compared to responders (p=0.05) suggesting this phenomenon is observed in cell lines, mouse models and primary samples. Finally, we investigated whether JAKper cells remain JAK2 dependent. Studies with shRNA targeting JAK2 and pharmacologic studies using Hsp90 inhibitors that degrade JAK2 protein demonstrate that JAK2 inhibitor persistent cells remain dependent on JAK2 protein expression. Our data indicate that JAK2/MPL mutant cells persist in the presence of JAK2 kinase inhibitors through epigenetic alterations which reactivate signaling in persistent cells, and that therapies which lead to JAK2 degradation can be used to inhibit signaling and improve outcomes in patients with persistent disease despite chronic JAK2 inhibition. Disclosures: Verstovsek: Incyte Corporation: Research Funding.

Meyer, Sara C., Matthew D. Keller, Priya Koppikar, Olga A. Guryanova, Maria Kleppe, Anna Sophia McKenney, William R. Sellers et al. "Type II Inhibition of JAK2 with NVP-CHZ868 Reverses Type I JAK Inhibitor Persistence and Demonstrates Increased Efficacy in MPN Models". Blood 124, n. 21 (6 dicembre 2014): 160. http://dx.doi.org/10.1182/blood.v124.21.160.160.

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Abstract The identification of JAK2 mutations in patients with myeloproliferative neoplasms (MPN) led to the clinical development of JAK2 inhibitors, and the JAK1/2 inhibitor ruxolitinib has been approved for the treatment of myelofibrosis (MF). Although clinically tested JAK inhibitors improve MPN-associated splenomegaly and systemic symptoms, they do not significantly reduce the MPN clone in most MPN patients.We previously demonstrated that MPN cells can acquire persistence to ruxolitinib and other type I JAK inhibitors which bind the active conformation of JAK2, and that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signaling and with heterodimerization between activated JAK2 and JAK1/TYK2, consistent with activation of JAK2 in trans by other JAK kinases. We have now extended our studies to other type I JAK inhibitors in clinical development, including CYT387, BMS911543 and SAR302503. In each case we see the same mechanism of persistence as observed with ruxolitinib, with transactivation of JAK2 by other JAK kinases. Most importantly, we found that MPN cells which were persistent to one JAK inhibitor were insensitive to the other JAK inhibitors, suggesting that the mechanisms which limit overall efficacy of ruxolitinib will limit the efficacy of other JAK inhibitors in clinical development. All JAK inhibitors in clinical development are type I inhibitors that interact with and inhibit the active confirmation of the JAK2 kinase. We hypothesized that novel, type II JAK inhibitors that interact with and inhibit JAK2 in the inactive conformation might retain activity in JAK inhibitor persistent cells and show increased efficacy in murine MPN models. We therefore characterized the efficacy of NVP-CHZ868, a novel type II JAK inhibitor, in MPN cells and in murine MPN models. CHZ868 potently inhibited proliferation of cells expressing the JAK2V617F mutation or the TEL-JAK2 fusion. We found that JAK2/MPL-mutant cell lines were universally sensitive to NVP-CHZ868. CHZ868 treatment of JAK2-mutant SET2 cells induced a higher degree of apoptosis compared to ruxolitinib. Signaling studies demonstrated that CHZ868 more potently attenuated JAK-STAT signaling in JAK2/MPL-mutant cells, with suppression of JAK2 phosphorylation consistent with a type II mechanism of kinase inhibition. We next investigated the ability of CHZ868 to inhibit the proliferation and signaling of MPN cells that had acquired persistence to type I JAK inhibitors. Type II inhibition with CHZ868 completely suppressed JAK-STAT signaling in type I JAK inhibitor-persistent cells, and prevented heterodimeric activation of JAK2 by JAK1 and TYK2. Most importantly, JAK2/MPL-mutant cells which were insensitive to type I JAK inhibitors remained highly sensitive to CHZ868, demonstrating that type I JAK inhibitor persistence does not confer resistance to type II inhibitors. We next evaluated the efficacy of CHZ868 in murine models of JAK2/MPL-mutant MPN. CHZ868 showed significant activity in conditional knock-in and bone marrow transplant (BMT) models of Jak2V617F-induced polycythemia vera, with normalization of hematocrit, reversal of stem/progenitor expansion, normalization of splenomegaly/splenic architecture, and reversal of bone marrow fibrosis. CHZ868 demonstrated similar activity in the MPLW515L BMT model of MF, with normalization of blood counts, stem/progenitor expansion, spleen weights, and extramedullary hematopoiesis in vivo. Most importantly, CHZ868 resulted in significant reductions of mutant allele burden (mean allele burden reduction 49%) in the Jak2V617F model. We observed analogous reductions in allele burden in the Jak2V617F and MPLW515L BMT models, consistent with disease modifying activity. Taken together, our data demonstrate that a spectrum of type I JAK inhibitors induce JAK inhibitor persistence, by a similar mechanism of JAK2 transactivation as observed with ruxolitinib. By contrast, type II JAK inhibition with CHZ868 remains highly active in JAK inhibitor persistent cells, and shows increased activity in murine MPN models. These data demonstrate that novel JAK inhibitors can increase target inhibition and therapeutic efficacy and should be pursued as an approach to improve outcomes for MPN patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Koppikar: Amgen: Employment. Sellers:Novartis: Employment. Hofmann:Novartis: Employment. Baffert:Novartis: Employment. Gaul:Novartis: Employment. Radimerski:Novartis: Employment. Levine:Novartis: Consultancy, Grant support Other.

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Tesi sul tema "JAK/STAT inhibitors":

Etter, Jonathan Parker. "Development of Inhibitors in the IL-6/GP130/JAK/STAT Pathway as Therapeutic Agents". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376525461.

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Gomes, Guilherme Wataru. "Expressão gênica dos transportadores de membrana ABCB1,ABCG2, SLC22A1 e SLCO1A2 em linhagens celulares tratadas com inibidor comercial da via JAK-STAT". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-16032016-095918/.

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INTRODUÇÃO: A desregulação da via de sinalização JAK-STAT é uma característica marcante das neoplasias mieloproliferativas (NMPs), doenças clonais da célula tronco hematopoética, dentre as quais encontra-se a mielofibrose (MF). Diversos inibidores de JAK foram desenvolvidos para o tratamento da MF e encontram-se em diferentes fases de desenvolvimento clínico. Devido ao seu desenvolvimento recente, pouco se sabe a respeito do papel de transportadores de membrana na farmacocinética desses compostos. Essas proteínas realizam o influxo e efluxo celular de substratos endógenos e xenobióticos, e alterações na expressão desses transportadores podem influenciar a resposta a esses fármacos. OBJETIVO: Avaliar o efeito de um inibidor comercial da via JAK-STAT na expressão gênica dos transportadores de membrana ABCB1, ABCG2, SLC22A1 e SLCO1A2 em células HepG2, Caco-2 e HEL92.1.7. MÉTODOS: Linhagens de carcinoma hepatocelular (HepG2), adenocarcinoma colorretal (Caco-2) e eritroleucemia humana homozigotas para JAK2V617F (HEL92.1.7) foram cultivadas e tratadas o inibidor comercial da via JAK-STAT JAK Inhibitor I. Para determinar a concentração ideal para o tratamento com o inibidor, as células foram tratadas com diversas concentrações do inibidor de JAK por 24 horas e foram feitos testes de viabilidade celular e fragmentação do DNA. Com as condições de tratamento padronizadas, foi extraído o RNA total das células e sintetizado o cDNA, para análise das expressões de RNAm dos genes ABCB1, ABCG2, SLC22A1 e SLCO1A2 por PCR em tempo real. Foi também avaliada a expressão dos transportadores de efluxo ABCB1 e ABCG2 por citometria de fluxo, utilizando anticorpos primários direcionados a essas proteínas. RESULTADOS: Nas células HepG2, foi observado um aumento da expressão de RNAm de ABCB1 nas células tratadas com 4,00 µM do inibidor de JAK, quando comparado com o controle (células incubadas apenas com o veículo) (P=0,041). Não foi observada alteração da expressão de RNAm de ABCG2 e SLC22A1 com o tratamento com o inibidor de JAK nessa linhagem (P>0,05); a expressão de RNAm de SLCO1A2 não foi detectada nessa linhagem. Nas células Caco-2, a expressão de ABCB1, ABCG2, SLC22A1 e SLCO1A2 não se alterou com o tratamento com o inibidor de JAK nas concentrações utilizadas (0,25 µM a 1,00 µM) por 24 horas (P>0,05). Para as células HEL92.1.7, não foi observada diferença na expressão de RNAm de ABCB1, ABCG2 e SLC22A1 com o tratamento com 1,00 µM do inibidor de JAK por 24 horas em comparação ao controle (P>0,05); nessa linhagem, a expressão de RNAm de SLCO1A2 não foi detectada. A expressão proteica dos transportadores ABCB1 e ABCG2 não sofreu alteração com o tratamento com o inibidor de JAK nas condições utilizadas nas três linhagens celulares estudadas (P>0,05). CONCLUSÕES: Apenas as células HepG2 apresentaram um aumento da expressão de RNAm do transportador de efluxo ABCB1 em concentrações elevadas do inibidor de JAK, sugerindo que os inibidores de JAK podem modular a expressão do gene desse transportador no fígado. O tratamento com o inibidor da via JAK-STAT não foi associado com alterações na expressão proteica de ABCB1 e ABCG2 em todas as células estudadas.
BACKGROUND: JAK-STAT pathway signaling disregulation is a hallmark of myeloproliferative neoplasms (MPN), hematopoietic stem cell clonal diseases, among which is myelofibrosis (MF). Several JAK inhibitors have been developed for MF treatment and are found in different stages of clinical development. Because the recent development of these compounds, the role of drug transporters in their pharmacokinetics is poorly understood. These proteins perform celular influx and effux of endogenous substrates and xenobiotics, and changes in the expression of these drugs transporters may affect the response to these drugs. AIM: To evaluate the effect of a JAK-STAT pathway commercial inhibitor in gene expression of drug transporters ABCB1, ABCG2, SLC22A1 and SLCO1A2 in HepG2, Caco-2 and HEL92.1.7 cells. METHODS: Hepatocellular carcinoma cell line HepG2, colorectal adenocarcinoma cell line Caco-2 and human erythroleukemia homozygous JAK2V617F cell line HEL92.1.7 were grown and treated with the JAK-STAT pathway inhibitor JAK Inhibitor I. In order to determine the optimal concentration for treatment with the inhibitor, cells were treated with several concentrations of JAK inhibitor by 24 hours, and cell viability and DNA fragmentation tests were performed. Once the treatment conditions were standardized, total RNA were obtained from the cells, and cDNA was synthesized in order to evaluate the mRNA expression of ABCB1, ABCG2, SLC22A1 and SLCO1A2 genes, performed by real time PCR. We also evaluate the expression of drug efflux transporters ABCB1 and ABCG2 by flow cytometry, using primary antibodies directed to these proteins. RESULTS: In HepG2 cells, it was observed an increase in ABCB1 mRNA expression in cells treated with 4,00 µM of JAK inhibitor, when compared with controls (cells exposed only to the vehicle) (P=0.041). There was no change in ABCB2 and SLC22A1 mRNA expression with the treatment with JAK inhibitor in this cell line (P>0.05); SLCO1A2 mRNA was not detected in this cell line. In Caco-2 cells, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression did not change with treatment with the JAK inhibitor at the concentrations used (0.25 µM to 1.00 µM) by 24 hours (P>0.05). In HEL92.1.7 cells, it was not observed differences in ABCB1, ABCG2 and SLC22A1 mRNA expression with the treatment with 1 µM of JAK inhibitor by 24 hours when compared with controls (P>0.05); in this cell line, SLCO1A2 mRNA was not detected. Protein expression of ABCB1 and ABCG2 drug transporters has not changed with treatment with the JAK inhibitor under the conditions used in the three cell lines studied. CONCLUSIONS: Only HepG2 cells presented an increase in mRNA expression of drug efflux transporter ABCB1 in presence of high levels of JAK inhibitor, suggesting that JAK inhibitors could modulate this transporter gene expression in liver. Treatment with JAK-STAT pathway inhibitor was not associated with changes in ABCB1 and ABCG2 protein expression in all cell lines studied.

Ghafoory, Shima. "Development of a screening assay for inhibitors of inflammation useful against pancreatic cancer". Thesis, Mälardalen University, Mälardalen University, School of Sustainable Development of Society and Technology, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-7797.

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Pancreatic cancer is the fourth most lethal cancer and ranks as the eighth most commonly diagnosed cancer worldwide. This is due to its rapid proliferation, strong metastatic potential and its delayed detection. One major risk factor for developing pancreatic cancer is the aggressive inflammatory disease chronic pancreatitis. Chronic inflammation frequently precedes the development of certain pancreatic cancers.

Inflammation is a protective and necessary process by which the body can alert the immune system of the existence of a wound or infection and mount an immune response to remove the harmful stimuli and start wound healing. The cross-talking of cells of the immune system and infected cells happens through cytokines, soluble proteins that activate and recruit other immune cells to increase the system’s response to the pathogen. Failure to resolve the injury can result in persistent cytokine production that in turn allows a cell that is damaged or altered to survive when in normal conditions it would be killed. Inflammation is thought to create a microenvironment that facilitates the initiation and/or growth of pancreatic cancer cells.

Cytokines use two important kinases for their signaling: Janus Kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs). The JAKs are activated upon the binding of cytokines to their corresponding receptors. When activated, the JAKs activate STATs through tyrosine phosphorylation. The STATs transduce signals to the nucleus of the cells to induce expression of critical genes essential in normal physiological cellular events such as differentiation, proliferation, cell survival, apoptosis and angiogenesis. STAT3 (a member of the STAT family) is constitutively activated in some pancreatic cancers, promoting cell cycle progression, cellular transformations and preventing apoptosis. Therefore, STAT3 is a promising target for cancer treatment. Novel therapies that inhibit STAT3 activity in cancers are urgently needed. Natural products are a very good resource for the discovery of new drugs against pancreatic cancer.

Covering more than 70% of the Earths surface, The Ocean is an excellent source of bioactive natural products. Harbor Branch Oceanographic Institute’s Center for Marine Biomedical and Biotechnology Research (HBOI-CMBBR) situated in Florida, aims to find new marine natural products useful in disease prevention and drug therapy. Their current focus is to look for novel treatments for preventing both the formation of new pancreatic tumors and the metastasis of existing tumors.

The hypothesis of this degree project was that novel inhibitors of STAT3 useful in the treatment of pancreatitis and/or pancreatic cancer could be found from marine-natural products. The first specific aim of this degree project was to set up an assay to identify bioactive marine natural products as inhibitors of inflammation. Furthermore the assay was validated using a commercially available inhibitor of inflammation (Cucurbitacin I). The last aim was to further validate the assay by screening pure compounds and peak library material from the HBOI marine specimen collection.

At the end of the experimentation time, the assay still was not set-up as there were difficulties in proper cell culture techniques and the cell line did not respond as advertised. While the results were not as expected, the work performed resulted in familiarization with research laboratory practices and increased laboratory skills. Moreover, the results from the assays point to future directions to accomplish this project.

Development of a screening assay for inhibitors of inflammation useful against pancreatic cancer

Berrabah, Sofia. "Etude de nouvelles cibles thérapeutiques dans les lymphomes compliquant la maladie cœliaque". Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5201.

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La maladie cœliaque réfractaire de type II (MCRII), autrement appelé lymphome intraépithélial, est une complication rare mais sévère de la maladie cœliaque caractérisée par une expansion clonale d'une population particulière de lymphocytes intraépithéliaux (LIE) innés, présents dans l'intestin normal chez l'Homme comme chez la souris. Notre laboratoire a montré que cette population particulière de LIE innés partage des caractéristiques communes à celles des lymphocytes T et des cellules NK. Ces « LIE iCD3+ innés » sont caractérisées par une expression de CD3 au niveau intracellulaire mais pas à la surface, de récepteurs NK et présentent des réarrangements des gènes codant le récepteur T. En outre, le laboratoire a montré que ces cellules se développent dans l'épithélium intestinal à partir de précurseurs de la moëlle osseuse en réponse à une combinaison de signaux induits à travers la voie NOTCH et l'interleukine 15. Durant la lymphomagénèse, les LIE iCD3+ innés acquièrent des mutations somatiques gain-de-fonction dans JAK1et/ou STAT3. Ces mutations pourraient favoriser l'expansion clonale des LIE iCD3+ mutés aux dépens des lymphocytes T normaux résidents en leur conférant une sensibilité accrue à l'interleukine 15 (IL-15), une cytokine surexprimée dans l'intestin des patients. Ainsi, notre hypothèse est que ces mutations ont un rôle central dans l'initiation de la lymphomagénèse dans un contexte de production chronique d'IL-15 et, de ce fait, représentent une cible thérapeutique. Le premier objectif de ma thèse a été d'étudier l'intérêt des inhibiteurs de la voie JAK/STAT dans le traitement de la MCRII. Dans un premier temps, nous avons testé in vitro différents inhibiteurs de JAK/STAT sur des lignées cellulaires IL-15-dépendantes issues soit de LIE de MCRII soit de LIE T normaux. Nous avons démontré que ces drogues inhibent la prolifération et la phosphorylation de STAT3 et augmentent l'apoptose cellulaire aussi bien dans les LIE MCRII que dans les LIE T normaux. Dans un second temps, nous avons généré un modèle de xénogreffe en injectant des cellules issues de biopsies intestinales ou du sang d'un patient MCRII dans des souris immunodéficientes surexprimant l'IL-15 humaine dans l'épithélium intestinal (Rag-/-Gc-/-IL-15TgE ou IRGC) afin de tester l'efficacité des inhibiteurs de JAK/STAT in vivo. Le traitement des souris xénogreffées par le ruxolitinib, inhibiteur de JAK1/JAK2, a permis une diminution de la fréquence et du nombre ainsi que de l'activité cytotoxique des cellules tumorales humaines et une amélioration de l'état général des souris. Ces résultats encourageants restent à confirmer. Le second objectif de ma thèse a été de vérifier si la mutation pD661V de STAT3 était suffisante pour induire le développement de la MCRII dans un contexte de surproduction d'IL-15 dans des souris IRGC. Nous avons généré avec succès les LIE iCD3+ innés murins semblables aux LIE iCD3+ innés humaines à partir de précurseurs communs aux cellules lymphoïdes (CLP) en combinant un signal NOTCH et IL-15. Nous avons ensuite transduit les CLP avec un vecteur rétroviral contenant Stat3 sauvage ou muté (D661V). Les cellules transduites ont alors été injectées chez des souris IRGC suivies pendant 8 semaines. Les résultats préliminaires ont montré que les LIE iCD3+ innés se logent préférentiellement dans l'intestin mais aucun développement d'un lymphome intraépithélial n'a été observé au bout de 8 semaines suggérant que la mutation pD661V de STAT3 seule ne suffit pas en présence d'IL-15 à induire in vivo un lymphome intraépithélial. Ces résultats préliminaires sont toutefois à reproduire et à confirmer. Le modèle mise en place pour l'étude de STAT3 va désormais être utilisé afin d'évaluer la contribution respective de mutations canoniques de JAK1 et STAT3 et des autres mutations récurrentes retrouvées dans le lymphome intraépithélial
Refractory coeliac disease type II (RCDII), also called intraepithelial lymphoma, is a rare but severe complication of coeliac disease characterized by the clonal expansion of a small subset of innate intraepithelial lymphocytes (IEL), present in the normal human and murine intestine. Our lab has shown that this population displays shared features between T and natural killer (NK) cells. These so-called iCD3+ innate IEL are mainly characterized by intracellular expression of CD3, which is not detected at the cell surface, expression of NK receptors as well as DNA rearrangement of T cell receptor genes. Our lab has also shown that iCD3+ innate IEL originate from bone marrow precursors through coordinated NOTCH1 and interleukin (IL)-15 signals. During lymphomagenesis, iCD3+ innate IEL of most RCDII patients were shown to have acquired somatic gain-of-function mutations in JAK1 and/or STAT3 that confer increased sensitivity to interleukin-15, a cytokine overexpressed in the intestine of coeliac patients, thereby promoting their clonal expansion. Thus, our hypothesis is that JAK1/STAT3 mutations play a key role in initiating lymphomagenesis associated to coeliac disease in an IL-15-rich environment and that they could represent an attractive therapeutic target.The first objective of my thesis was to study the interest of JAK/STAT inhibitors for RCDII treatment. First, we have tested in vitro different JAK/STAT inhibitors on IL-15-dependent RCDII or normal IEL-T cell lines. We have shown that these inhibitors decrease the proliferation and phosphorylation of STAT3 and increase cellular apoptosis in both RCDII and normal T cell lines. Secondly, we have established a xenograft model based on the injection of cells derived from biopsy or blood from one RCDII patient into immunodeficient mice overexpressing the human IL-15 transgene in their gut epithelium (Rag-/-Gc-/- IL-15TgE; IRGC) to test the efficacy of JAK/STAT inhibitors in vivo. Treatment of xenografted mice with ruxolitinib, a potent inhibitor of JAK1/JAK2 decreased the frequency, number and cytotoxic potential of human tumoral cells and allowed clinical restoration. These preliminary results are encouraging but need to be confirmed. The second objective of my thesis was to test whether the Stat3 pD661V mutation is sufficient to induce the intraepithelial lymphoma in an IL-15-rich context in IRGC mice. We have successfully generated murine iCD3+ innate IEL in vitro, resembling their human counterparts from common lymphoid precursors by combining NOTCH and IL-15 signals. We then transduced CLP with a retroviral vector containing wild-type or mutated Stat3 pD661V. The transduced cells were injected into IRGC mice that subsequently were followed-up during a period of 8 weeks. In vitro generated iCD3+ innate IEL preferentially homed to the intestine. However, no development of intraepithelial lymphoma was observed suggesting that the Stat3 pD661V variant alone is not sufficient to induce the intraepithelial lymphoma. These preliminary results need to be reproduced and confirmed. The murine model used to test the role of STAT3 will now be used to evaluate the respective contribution of canonical mutations in JAK1 and STAT3 and of other recurrent mutations identified in RCDII

Younis, Usir, e Usir Younis. "Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems". Diss., The University of Arizona, 2018. http://hdl.handle.net/10150/626756.

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Asthma is a significant lung disease involving chronic inflammation and remodeling of the airways, resulting in reduced quality of life for those who suffer from the condition. Current therapeutic guidelines suggest the use of inhaled corticosteroids for long-term anti-inflammatory relief to manage moderate to severe chronic asthma; however, inhaled corticosteroids fail to provide prophylactic or reversal treatment of damaged airways incurred by chronic asthma as well as exhibiting adverse side effects (skeletal complications, diabetes, and weight gain).Therefore, there is a need for a new type of drug therapy to address these gaps in the treatment of chronic asthma. There is growing interest aimed towards the inhibition of the Janus Kinase and Signal Transducer and Activator of Transcription (JAK-STAT) pathway for the treatment of asthma. Despite the promising opportunity to investigate this new pathway towards this clinical application, no published work is available using an established and characterized JAK 1/3 inhibitor for the treatment of chronic asthma delivered via inhalation. This work investigated tofacitinib citrate, a selective JAK 3 inhibitor, and its potential to be delivered locally to the lungs for the treatment of chronic asthma. Several preformulation studies were conducted to determine the basic physical and chemical properties of the compound and its free base, tofacitinib, for proper inhalational formulation development. The drug was delivered to BALB/c mice challenged with house dust mite (HDM) allergen via nebulization utilizing a nose-only chamber. After a three week dosing schedule, mice treated with tofacitinib citrate exhibited an increase in monocyte cell numbers with a simultaneous decrease in eosinophil cell count, gathered from BAL fluid. Further, the experimental groups treated with tofacitinib citrate had a decrease in total protein concentrations in comparison to the experimental groups that were only challenged with HDM or were both exposed to HDM and vehicle. These findings demonstrated that the proper formulation was developed for nebulized delivery of tofacitinib citrate, and that the compound was capable of reducing total protein concentrations and eosinophil cell recruitment, both recognized as biomarkers for an asthmatic response. Although significant work is still needed to be done, these data hold promise for the potential of a locally delivered JAK 3 inhibitor as a treatment for chronic asthma. Further, the solubility of tofacitinib citrate and five other pharmaceutical salts were determined in HFA 134a, HFA 227, and DFP with varying cosolvent content (0-20% v/v ethanol). The experimental solubilities of the free acid and base compounds were larger than the solubilities of their respective salts in all three systems for tofacitinib, albuterol, and salicylic acid. Warfarin, phenytoin, and ciprofloxacin had similar solubilities with their respective salt forms. Solubilities also increased with increasing cosolvent concentration for all compounds investigated. The model propellant, DFP, provided a slightly stronger correlation of solubility values with HFA 134a in comparison to HFA 227. The observed solubility values were also compared to calculated values obtained from the ideal solubility model, where it was determined that the observed solubility was indeed also dependent on its surrounding solvent interactions and not solely on its ideal solubility (melting point). While some physical changes were observed for the pharmaceutical salts in HFA 134a and 227, more quantitative studies are needed for a larger database of compounds to better understand the factors that contribute to the solubility of pharmaceutical salts (and their correlation to DFP), in HFA-based systems. This information could potentially contribute to a predictive model, saving time and money during the process of pMDI formulation development.

Jark, Paulo César [UNESP]. "Estudo da via jak2/stat3 e de seus inibidores em linfomas multicêntricos difusos de grandes células B caninos". Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/146685.

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A via Janus Kinase (JAK) e do transdutor de sinal e ativador de transcrição (STAT) desempenham papéis importantes na patogênese de neoplasias hematopoiéticas. A ativação da via JAK2/STAT3 promove o crescimento e sobrevivência celular em uma variedade de linfomas humanos. Há uma necessidade de compreender a participação da via JAK2/STAT3 em linfomas caninos difusos de grandes células B e do potencial terapêutico dos inibidores de JAK no tratamento dessa doença. O objetivo do presente estudo foi avaliar a expressão de JAK2-STAT3 em linfomas difusos de grandes células B e o impacto do uso de inibidores de JAK2 como AZD1480 e CYT387 no crescimento in vitro dessa linhagem tumoral. Foi realizada técnica de imuno-histoquímica com os anticorpos anti-STAT3 e anti-STAT3 fosforilado (p-STAT3) em linfonodos acometidos por linfoma difuso de grandes células B e comparado à linfonodos normais e reativos. Para avaliação do efeito terapêutico dos inibidores de JAK2 (AZD1480 e CYT387) foi realizado ensaio de viabilidade celular pelo método de azul de tripan utilizando linhagens celulares de linfoma difuso de grandes células B (CLBL-1) e análise de apoptose por citometria de fluxo utilizando o sistema Annexin V. Houve aumento significativo na expressão de STAT3 e p-STAT3 em linfomas difusos de grandes células B em comparação com linfonodos normais. Ambos os fármacos inibiram o crescimento celular em proporções dependentes da dose administrada e houve um aumento significativo nas taxas de apoptose das células tratadas com inibidores de JAK-2 em comparação ao grupo controle tratado com DMSO. Este é o primeiro estudo a avaliar a via JAK2/STAT3 em linfomas difusos de grandes céluslas B canino e esses dados permitem compreender e explorar o potencial terapêutico dos inibidores de JAK permitindo estudos futuros da eficácia clínica desses fármacos na oncologia veterinária
The Janus Kinase (JAK) and signal transducer and activator of transcription (STAT) pathway play important roles in the pathogenesis of hematologic malignancies. Activated JAK2-STAT3 signaling pathway promotes the growth and survival of a variety of lymphomas in human. There is a great demand for understanding JAK-STAT pathway in canine diffuse large B cell lymphoma (DLBCLs) and evaluating the therapeutic potential of JAK inhibitors. Our study aims to evaluate the expression of JAK2-STAT3 pathway in canine DLBCLs and to assess the impact of AZD1480 and CYT387, two novel JAK inhibitors, on canine DLBCL cell growth. Immunohistochemistry was performed in canine DLBCLs, normal and reactive lymph nodes with primary antibodies against STAT3 and phosphorylated STAT3 (p-STAT3). To evaluate the therapeutic effect of novel JAK inhibitors, canine DLBCL cell line CLBL-1 was treated with either AZD1480 or CYT387 and trypan blue viability assay was performed post treatment. There was a significant increase in expression of STAT3 and pSTAT3 in canine DLBCLs compared with the normal lymph node. Both AZD1480 and CYT387 inhibited canine DLBCL cells in a dose dependent manner. This is the first study to evaluate the JAK2/STAT3 pathway in canine DLBCLs. The knowledge of JAK2-STAT3 activity in canine DLBCLs enables us to understand and explore the therapeutic potential of JAK inhibitors. The dose dependent cell growth inhibition by novel JAK inhibitors in this study will lead into the future studies of the underlying mechanism

Albrengues, Jean. "Rôle de la cytokine Leukemia Inhibitory Factor (LIF) dans l'activation et le maintien des fibroblastes pro-invasifs lors de la carcinogénèse". Thesis, Nice, 2014. http://www.theses.fr/2014NICE4107/document.

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Le stroma inflammatoire joue un rôle primordial lors de la carcinogénèse. Dans ce contexte, nous montrons que la cytokine LIF est à l'origine d'une population de fibroblastes capable de remodeler la matrice extracellulaire de manière à la rendre permissive à l'invasion collective des cellules tumorales. En effet, nous montrons que la production de LIF par les cellules tumorales et fibroblastiques, après une stimulation au TGFβ, va réguler les capacités contractiles et pro-invasives de ces dernières via la régulation du cytosquelette d'acto-myosine et de manière indépendante de l'expression de α-SMA. En effet, l'inhibition pharmacologique des kinases JAKs permet de bloquer l'environnement fibrotique des tumeurs et d'ainsi bloquer l'invasion des cellules tumorales in vitro et in vivo. Nous montrons ensuite que LIF est à l'origine d'un switch épigénétique responsable de l'activation constitutive de la voie de signalisation JAK1/STAT3. Ce processus, régulé par la forme acétylée de STAT3, et son interaction avec l'ADN methyltransférase DNMT3b permet l'hypermethylation du promoter de la phosphatase SHP1 et donc la phosphorylation constitutive de JAK1. Une fois mis en place, ce nouveau profil de méthylation est maintenu par DNMT1. La surexpression de LIF dans les carcinomes humains corréle avec un environnement fibrotique, la présence de nodules invasifs et un mauvais pronostic clinique. De même, il existe une forte corrélation négative entre l'acétylation de STAT3 et l'expression de SHP1 dans le stroma tumoral. Nos résultats montrent qu'inhiber l'activité des DNMT et des kinases JAK permet de reprogrammer les capacités pro-invasive des fibroblastes associés aux carcinomes
Signaling crosstalk between tumor cells and fibroblasts confers proinvasive properties to the tumor microenvironment. We identify LIF as a tumor promoter that mediates proinvasive activation of stromal fibroblasts independent of alpha-smooth muscle actin expression. We demonstrate that a pulse of transforming growth factor β (TGF-β) establishes stable proinvasive fibroblast activation by inducing LIF production in both fibroblasts and tumor cells. In fibroblasts, LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, which results in collective carcinoma cell invasion. Indeed, pharmacological inhibition of JAK activity by counteracts fibroblast-dependent carcinoma cell invasion in vitro and in vivo. We next unveil that LIF initiates an epigenetic switch leading to the constitutive activation of JAK1/STAT3 signaling, which results in sustained pro-invasive activity of fibroblasts. The process is mediated by p300-histone acetyltransferase acetylation of STAT3, and DNA methyltransferase DNMT3b, which induce the hypermethylation of SHP1 phosphatase promoter and results in constitutive phosphorylation of JAK1. Sustained JAK1/STAT3 signaling is maintained by DNMT1. Accordingly, carcinomas display strong LIF upregulation, which correlates with dense collagen fiber organization, cancer cell collective invasion, and poor clinical outcome. Moreover, we show that STAT3 acetylation and phosphorylation are inversely correlated with SHP1 expression in tumors stroma. Combined inhibition of DNMT activities and JAK signaling results in long-term reversion of CAF-associated pro-invasive activity and restoration of the wild-type fibroblast phenotype

Miller, Daniel M. "Human cytomegalovirus inhibits interferon stimulated antiviral and immunoregulatory responses by disrupting JAK-STAT signal transduction : a novel mechanism of cytomegalovirus persistence /". The Ohio State University, 1998. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487953567769393.

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Hussain, Shabbir. "Mycobacterium Avium infection of mouse macrophages inhibits interferon-gamma jak-stat signaling and gene induction by down-regulation of interferon-gamma receptor /". The Ohio State University, 1999. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488187049540245.

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Jungalee, Anouchka. "Implication physiopathologique de l'adaptateur LNK : mécanismes d'action et perspectives thérapeutiques dans les Néoplasmes Myéloprolifératifs". Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCD017/document.

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L’adaptateur LNK est un régulateur négatif des voies de signalisation, dont la voie JAK/STAT,essentielle au développement du système hématopoïétique. Son implication dans les hémopathies chroniques, notamment les Néoplasmes Myéloprolifératifs (NMP), a été mise en évidence par l’analyse de souris invalidées pour cet adaptateur et l’identification de mutations de LNK chez les patients atteints de ces pathologies. Toutefois, le mécanisme permettant la régulation de ses partenaires, dont la kinase JAK2, et l’implication fonctionnelle des mutations de LNK dans les NMP, restent à définir. Ainsi, mon projet de thèse a porté sur l’analyse structurale et fonctionnelle des complexes de signalisation LNK/JAK2 et sur le développement d’une stratégie moléculaire pour l’utilisation thérapeutique de LNK dans les NMP. Nos résultats ont montré pour la première fois, la fonction inhibitrice de la région N-terminale incluant le domaine d’homologie à la Pleckstrine deLNK sur JAK2 normale et de manière plus importante, sur la forme mutée JAK2-V617F, retrouvée chez les patients atteints de NMP. De plus, nos études sur les mutations de LNK localisées dans cette région régulatrice, ont permis de comprendre leur contribution dans le développement de ces hémopathies et de proposer un mécanisme d’inhibition de l’activation de JAK2 par LNK. Nos résultats permettent d’utiliser le ciblage de la région N-terminale de LNK comme stratégie moléculaire inhibant spécifiquement la forme oncogénique JAK2-V617F à l’aide de peptides pénétrants (CPP). A long terme, cette approche pourrait être utilisée comme outil thérapeutique dans le traitement de patients atteints de NMP positifs pour JAK2-V617F
The LNK adaptor protein is a key negative regulator of signalling pathways, such as JAK/STAT, important in the development of the hematopoietic system. Its implication in chronic blood diseases, such as Myeloproliferative Neoplasms (MPN) has been confirmed by studies on Lnk-deficient mice, as well as the identification of LNK mutations in MPN patients. However, the LNK mechanism of regulation on its partners and the functional implication of LNK mutations in MPN pathogenesis, are still unclear. Therefore, my PhD project covers the structural and functional analysis of theLNK/JAK2 signalling complex and the development of a molecular strategy to use LNK as a therapeutic tool for the treatment of MPN patients. Our study showed, for the first time, the inhibitory function of the N-terminal region and the pleckstrin homology domain of LNK on JAK2 activity, which occurs more importantly on JAK-V617F than JAK2 wild type form. Moreover, our study provided evidence on how LNK mutations located in this LNK region could contribute to these haematological diseases and has allowed us to propose a model for LNK regulatory function on JAK2activity. Furthermore, we developed a cell penetrating peptide-based strategy to deliver this regulatory region of LNK in hematopoietic cells to specifically inhibit JAK2-V617F oncogenic form. The finalaim is to use this region as a therapeutic molecule to treat JAK2-V617F-positive MPN patients

Libri sul tema "JAK/STAT inhibitors":

Fleischmann, Roy. Signalling pathway inhibitors. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0081.

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Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and SyK pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Tofacitinib is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2 while baricitinib (formerly INCB028050) predominantly inhibits JAK1/2. Many of the proinflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Fostamatinib disodium is an orally available inhibitor of spleen tyrosine kinase (SyK), which is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling may interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib has been investigated in multiple phase 2 and phase 3 trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα‎) and in patients who have failed TNFα‎ inhibitors. The efficacy of fostamatinib and baricitinib has been investigated in phase 2 trials; both are in large phase 3 clinical programmes. Each of these medications has demonstrated efficacy; their safety profile has been shown to be different from each other and from currently approved biological agents. This chapter discusses what is currently known and understood about their efficacy and safety.

Capitoli di libri sul tema "JAK/STAT inhibitors":

Yang, Jennifer, e Gregory B. Lesinski. "Curcumin Analogs as Inhibitors of the Jak-STAT Signal Transduction Pathway". In Novel Apoptotic Regulators in Carcinogenesis, 247–66. Dordrecht: Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-94-007-4917-7_10.

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Scott, Linda M. "Inhibitors of the JAK/STAT Pathway, with a Focus on Ruxolitinib and Similar Agents". In Resistance to Targeted Anti-Cancer Therapeutics, 107–34. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-75184-9_6.

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Borgés, Sahra, Elara Moudilou, Cécile Vouyovitch, Jean Chiesa, Peter Lobie, Hichem Mertani e Mireille Raccurt. "Involvement of a JAK/STAT Pathway Inhibitor: Cytokine Inducible SH2 Containing Protein in Breast Cancer". In Hormonal Carcinogenesis V, 321–29. New York, NY: Springer New York, 2008. http://dx.doi.org/10.1007/978-0-387-69080-3_30.

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Quinn, Michael R., Madhabi Barua, Yong Liu e Valeria Serban. "Taurine Chloramine Inhibits Production of Inflammatory Mediators and iNOS Gene Expression in Alveolar Macrophages; a Tale of Two Pathways: Part II, IFN-γ Signaling Through JAK/Stat". In Advances in Experimental Medicine and Biology, 349–56. Boston, MA: Springer US, 2003. http://dx.doi.org/10.1007/978-1-4615-0077-3_43.

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Fleischmann, Roy. "Signalling pathway inhibitors". In Oxford Textbook of Rheumatology, 630–35. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0081_update_003.

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Abstract (sommario):

Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and other pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Many of the pro-inflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Spleen tyrosine kinase (SyK) is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling should interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib, approved in many countries for the treatment of RA, is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2; there are other JAK inhibitors in development which are purported to be more specific for JAK3 (Vertex 509), specific for JAK1/2 (baricitinib) or more specific for JAK1 (Galapagos and INCYTE) where clinical data has been reported. Tofacitinib has been investigated in multiple clinical trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα‎‎) and in patients who have failed TNFα‎‎ inhibitors. Vertex 509 has been investigated as monotherapy or in combination with MTX in DMARD failures while baricitinib, GLPG0634 (Galapagos), and INCB039110 (Incyte) have been investigated in phase 1 and 2 clinical trials in combination with MTX. Each of these medications has demonstrated efficacy; their safety profile has been shown to be generally similar although with some differences from each other and some differences from most of the currently approved biological agents. Fostamatinib disodium is an orally available inhibitor of SyK which was investigated in multiple phase 3 clinical trials in RA but was found to be generally ineffective with significant safety signals. This chapter discusses what is currently known and understood about the efficacy and safety of these oral, small-molecule DMARDs.

Tantravahi, Srinivas K., Jamshid S. Khorashad e Michael W. Deininger. "Genomic landscape of myeloproliferative neoplasms". In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 15–31. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0002.

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The discovery of the Philadelphia chromosome (Ph) and BCR-ABL1 fusion gene in chronic myeloid leukaemia (CML) was a first step in understanding the genetic basis of myeloproliferative neoplasms (MPN), but it took more than 20 years until the molecular basis of Ph^– MPN was unravelled with the identification of mutually exclusive mutations in JAK2, MPL, and CALR. The common effect of these mutations, activation of JAK/STAT signalling, informed the therapeutic development of JAK kinase inhibitors. Additional mutations in epigenetic modifier, mRNA splicing, and transcriptional regulator genes are present in many MPN cases. Elucidating the prognostic and functional significance of these mutations is the focus of intense ongoing studies. Given that JAK kinase inhibitors have limited impact on the mutant allele burden these additional pathways may offer much needed additional therapeutic targets. In this chapter, we discuss in detail the genetic landscape of MPN in the context of prognostication and therapy.

Starr, Robyn. "Inhibitors Of The Janus Kinase – Signal Transducers And Activators Of Transcription ( Jak/ Stat) Signaling Pathway". In Cytokine Inhibitors. CRC Press, 2000. http://dx.doi.org/10.1201/9780203904244.ch10.

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Alsiary, Rawiah A., Talat Abdullah Albukhari e Waheed A. Filimban. "Transcription Factors in Cancer". In Molecular Targets and Cancer Therapeutics (Part 1), 273–319. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815080384123010010.

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Different types of signalling pathways have been approved to be involved in cancer imitation and progression. These signalling pathways include the JAK-STAT signalling, NF-κB signalling, Wnt, Notch and Hedgehog. STAT (Signal Transducer and Activator of Transcription) transports signals between proteins from the cell membrane into the nucleus to contribute to cancer progression. NF-κB signalling is essential for the survival of the B cell tumor types. The Wnt, Notch, and Hedgehog signalling pathways play a significant role in carcinogenesis by upregulating the genes associated with these pathways. Hence, pharmacological inhibitors of WNT, NOTCH, and HH pathways are required in clinical studies. Such inhibitors have features that make them important during the clinical trial since they offer great potential as novel therapeutics for cancer. They also have an antitumor response which should be taken into consideration. The three signalling pathways are also known to shape cell fate determination and differentiation. In case of depletion of a single molecular component within the three pathways, embryonic lethality will form.

Demir Çetinkaya, Büşra. "Targeting the SH2 Domain of STAT3 Proteins in Breast Cancer Treatment". In Current Researches in Health Sciences-II. Özgür Yayınları, 2023. http://dx.doi.org/10.58830/ozgur.pub128.c630.

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Stat proteins, transcription factors that convert extracellular stimuli into appropriate biological responses, are involved in many normal physiological cell processes, including proliferation, differentiation, apoptosis, angiogenesis, and immune system regulation. Irregular Stat activation is often associated with tumorigenesis. This situation has made the Stat pathway an interesting target for drug development studies in cancer treatment and has led to the development of various inhibitors targeting this pathway. Stat signal inhibitors are divided into two main groups as inhibitors with direct and indirect effects. Direct inhibitors target the SH domain, DNA binding domain, or N-terminal domain of the Stat3 protein; indirect inhibitors target upstream components of the Stat3 pathway, such as JAK2 and EGFR. It is known that Stat3 has a strong relationship with the formation of breast cancer and its permanent activation is most pronounced in breast cancer. In this study, primarily the components of the Stat signaling pathway, activation/inactivation and the functions of Stat3 were emphasized, the inhibitors that act by directly inhibiting the SH2 domain of Stat3 proteins in breast cancer cells were focused, and the results of the research examining the effects of these inhibitors on breast cancer cells were compiled.

Harrison, Claire, Yan Beauverd e Donal McLorran. "Myelofibrosis". In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 126–50. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0009.

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The World Health Organization (WHO) classification defines myelofibrosis (MF) to comprise of the three principal subtypes, primary myelofibrosis, post-polycythaemia vera myelofibrosis, and post-essential thrombocythaemia. Each subtype appears to exhibit a similar pathogenesis, clinical presentation, evolution, and treatment. The critical driver mutations involved in the pathogenesis are be JAK2, MPL, or CALR; mutations in the splicing machinery genes, the epigenome, transcription factors, and dysregulation in the haematopoietic stem cell niche also play pathogenetic roles. Myelofibrosis is a progressive disease, often evolves from a precursor disease state without any clinical symptoms and few laboratory anomalies, to more advanced stages with substantial symptom-burden. Janus kinase (JAK) inhibitors, such as ruxolitinib, afford significant symptomatic benefit, but no major impact on the JAK2 allelic burden, and many patients are offered a risk-adapted approach.

Atti di convegni sul tema "JAK/STAT inhibitors":

Fanouriakis, Antonis. "28 JAK-STAT inhibitors in systemic lupus erythematosus". In 12th Annual Meeting of the Lupus Academy; Virtual Pre-meeting: September 1, 2023; Hybrid Annual Meeting (Barcelona): September 8–10, 2023. Lupus Foundation of America, 2023. http://dx.doi.org/10.1136/lupus-2023-la.28.

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Hu, Wanting. "Progress of JAK/STAT 3 and its inhibitors in the treatment of cancer". In 2ND INTERNATIONAL CONFERENCE ON FRONTIERS OF BIOLOGICAL SCIENCES AND ENGINEERING (FSBE 2019). AIP Publishing, 2020. http://dx.doi.org/10.1063/5.0000440.

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Morena, Isabel de la, Juan Alberto Paz Solarte, Diego Bedoya e Pilar Trenor Larraz. "AB0435 REAL WORLD DATA OF A PATIENT COHORT WITH RHEUMATOID ARTRITIS TREATED WITH JAK/STAT INHIBITORS". In Annual European Congress of Rheumatology, EULAR 2019, Madrid, 12–15 June 2019. BMJ Publishing Group Ltd and European League Against Rheumatism, 2019. http://dx.doi.org/10.1136/annrheumdis-2019-eular.8254.

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Abdelhamid, Dalia, Mike Corcoran, Jonathan P. Etter, Sheng Hu, Bulbul Pandit, Chenglong Li, Pui-Kai Li e James R. Fuchs. "Abstract 4502: Synthesis and evaluation of curcumin-like compounds as inhibitors of the JAK/STAT pathway in cancer". In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4502.

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Covey, Todd M., Santosh Putta, Michael Gulrajani, Aileen C. Cohen e Alessandra Cesano. "Abstract B182: Single cell network profiling (SCNP) by flow cytometry as a tool to measure potency and selectivity of JAK/STAT inhibitors in PBMC and whole blood discrete cell subsets". In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-b182.

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Amin, ARM Ruhul, ASM Anisuzzaman, Abu B. Siddique e James R. Fuchs. "Abstract 680: FLLL12 is a small molecule JAK2 inhibitor that inhibits JAK-STAT3 pathway in head and neck cancer". In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-680.

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Chen, Huawei (Ray), Geraldine Bebernitz, Kirsten Bell, Erica Anderson, Nanhua Deng, Jason Kettle, Paul Lyne e Richard Woessner. "Abstract 4046: Targeting jak/stat adaptive mechanism with jak1 inhibitor azd4205 reduces residual disease and prolongs benefit of osimertinib". In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4046.

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De Velasco, Marco A., Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu et al. "Abstract 906: Therapeutic potential of JAK/STAT signal inhibition in prostate cancer by the JAK inhibitor AZD1480." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-906.

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Oh, Stephen T., Erin F. Simonds, Carol Jones, Matthew B. Hale, Yury Goltsev, Kenneth D. Gibbs, Jason D. Merker, James L. Zehnder, Garry P. Nolan e Jason Gotlib. "Abstract 239: Mutation of the inhibitory adaptor protein LNK drives potentiated JAK-STAT signaling in patients with JAK2 V617F-negative myeloproliferative neoplasms". In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-239.

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Silva Carmona, M. D., T. Vogel, S. Marchal, M. Guesmi, J. C. Dubus, M. Baravalle, S. Leroy et al. "Treatment of Interstitial Lung Disease in STAT3 Gain-of-Function Using JAK Inhibitors". In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a4376.

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Rapporti di organizzazioni sul tema "JAK/STAT inhibitors":

Tian, Cong, Jianlong Shu, Wenhui Shao, Zhengxin Zhou, Huayang Guo e Jingang Wang. The efficacy and safety of IL Inhibitors, TNF-α Inhibitors, and JAK Inhibitor on ankylosing spondylitis: A Bayesian network meta-analysis of a “randomized, double-blind, placebo-controlled” trials. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, settembre 2022. http://dx.doi.org/10.37766/inplasy2022.9.0117.

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Abstract (sommario):

Review question / Objective: In this study, we conducted a Bayesian network meta-analysis to evaluate the efficacy and safety of interleukin (IL) inhibitors, tumor necrosis factor-alpha (TNF-α) inhibitors, and Janus kinase (JAK) inhibitors on ankylosing spondylitis (AS).The purpose of this study is to compare the effectiveness and safety of different interventions for treating AS to provide insights into the decision-making in clinicalpractice. Condition being studied: Ankylosing spondylitis. Based on the Bayesian hierarchical model, we conducted a network meta-analysis using the gemtc package in R software (version 4.1.3) and Stata software (version 15.1). Cong Tian and Jianlong Shu contributed to the conception and design of the study and supervised the tweet classification. All authors drafted the manuscript. Wenhui Shao, Zhengxin Zhou, Huayang Guo and Jingang Wang contributed to data management and tweet classification. Cong Tian, Jianlong Shu and Zhengxin Zhou performed the statistical analysis. Cong Tian, Jianlong Shu, Wenhui Shao and Zhengxin Zhou reviewed the manuscript.