Cytokine Signalling Forum

Publications





October 20

Preclinical characterisation of itacitinib, a Novel Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

Covington M, He X, Scuron M, Li J, Collins R, Juvekar A, Shin N, Favata M, Gallagher K, Sarah S, Xue CB, Peel M, Burke K, Oliver J, Fay B, Yao W, Huang T, Scherle P, Diamond S, Newton R, Zhang Y, Smith.
European Journal of Pharmacology. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505

Itacitinib is an orally active JAK inhibitor and effectively delayed disease onset, reduced symptom severity, and accelerated recovery of inflammatory diseases in mouse models. Covington M et al demonstrated itacitinib’s high selectivity for JAK 1, its inhibition on IL-2 induced T cell proliferation and JAK/STAT signalling, its ability to also inhibit of the JAK/STAT pathway in response to IL-6 stimulation, and its effect on rat adjuvant induced arthritis model. The study used recombina...

July 17

Romatoid Artritde Hedeflenen Tedaviler 1�Romatoid Artrit Tedavisinden Patogenetik Anlayış

McInnes I, Schett G.
Lancet 2017;389:2328–37 DOI 10.1016/S0140-6736(17)31472-1

This review paper examines the understanding gained from looking at the effects of specific immune interventions in the treatment of RA. The introduction of novel IL-6 agents has provided the ideal opportunity to explore the distinct effect of cytokine inhibition, as opposed to receptor inhibition, at the molecular level. Mechanistic insights into TNF could also be obtained in the future with advanced molecular and informatics approaches, and future biopsy studies will be important to explore t...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

September 16

Deneysel Artrit Tedavisinde Doğal İmmün İnhibitörü İnterlökin-37 Eklem ve Sistemik İnflamasyonu Azaltır

Cavalli G, Koenders M, Kalabokis V, Kim J, Tan AC, Garlanda C, Manovani A, Dagna L, Joosten LAB, Dinarello CA.
Rheumatology (Oxford) 2016; DOI 10.1093/rheumatology/kew325

IL-37, a member of the IL-1 family, has recently been characterised as a fundamental inhibitor of innate inflammation. This study examines the effects of recombinant IL-37 on joint inflammation and pathology in a mouse model of arthritis, and also explores its potential in the treatment of human joint inflammation. In this mouse model of experimental arthritis, short-term, low-dose treatment with IL-37 suppressed joint and systemic inflammation. Wild-type mice received three intraperitoneal dos...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

May 16

Tofasitinibin günde bir kez kullanılan uzatılmış salınımlı formulasyonu: çabuk salınımlı tofasitinib ile farmakokinetik karşılaştırılması ve yemek etkisinin değerlendirilmesi

Lamba et al.
J Clin Pharmacol. 2016 Mar 11. doi: 10.1002/jcph.734. [Epub ahead of print]

PK profile of TOF is rapid absorption and elimination with time to max concentration 0.5-1 hour and terminal half-life at 3 hours. It is currently approved for immediate release (IR) 5 mg BID, 10 mg total; however, decreasing the dosage to QD dosing may help increase compliance. This study performed in 24 healthy males compared the PK of XR and IR TOF under both single and multiple dose conditions and evaluated the effect of a high-fat meal on the PK of XR TOF. There were no clinically importa...

Keywords: JAK, Tofacitinib, Preclinical, PK-PD

Translated by: Bahtiyar Toz

March 16

Erken Artrit de VPAC1 Reseptör Ekspresyonunun Klinik İlişkisi: IL-6 ve Hastalık Aktivitesi ile İlişkisi

Seoane I, Ortiz A, Piris L et al.
 PLoS ONE 11(2): e0149141. doi:10.1371/journal. pone.0149141

VPAC1 and VPAC2 both mediate anti-inflammatory and immunoregulatory responses in RA. Both these are receptors of vasoactive intestinal peptide (VIP), a broadly distributed peptide found in neural, endocrine and immune cells, which triggers biological response when interacting with the aforementioned receptors. It has recently been described in Martinez et al. that those patients with low levels of VIP have worse disease outcome.1 This study analyzed 250 blood samples from the Princesa early Art...

Keywords: IL-6, Preclinical

October 15

Tofacitinib STAT aktivasyonunun inhibisyonu ve negatif geri besleme inhibisyonunun indüksiyonu ile psöriatik artritteki sinoviyal inflamasyonu düzenler

W Gao, T McGarry, C Orr, J McCormick, D J Veale, U Fearon.
Annals of the Rheumatic Diseases. 2015 Sep 9. doi:10.1136/annrheumdis-2014-207201

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis (Ps) and characterised by synovitis and progressive destruction of articular cartilage and bone. Recently developed agents for PsA target IL12p40, IL-6 and IL-17, several of which signal through the JAK family of receptor-associated tyrosine kinases. Tofacitinib is a drug of the JAK inhibitor class and is currently approved for the treatment of RA in 27 countries. This study evaluated the effect of tofacitini...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Şafak Mirioğlu

Tocilizumab tedavisi alan romatoid artrit hastalarında hastalık aktivitesinin durumunu kalprotektin akut faz reaktanlarından daha iyi sağlar

José Inciarte-Mundo, Virginia Ruiz-Esquide, Maria Victoria Hernández, Juan D Cañete, Sonia Raquel Cabrera-Villalba, Julio Ramirez, Jordi Yagüe and Raimon Sanmarti.
Rheumatology. 2015 Aug 4. doi:pii: kev251. [Epub ahead of print]

Calprotectin is a member of the S100 protein family that has strong pro-inflammatory effects that reflect local ongoing inflammation rather than systemic response, due to its release at local inflammation sites. High calprotectin levels have been found in SF and serum from RA patients and correlate with disease activity. This study analysed the accuracy of calprotectin compared to acute phase response in discriminating the clinical disease status of RA patients receiving TCZ. A clinical assessme...

Keywords: IL-6, Tocilizumab, Preclinical, MOA

Translated by: Bahtiyar Toz

June 15

TNF-α ve IL-6 ‘nın  inflamatuar artritli eklemlerde Dkk-1 regülasyonu farklıdır

Yeremenko N, Zwerina K, Rigter G, Pots D, Fonseca J, Zwerina J, Schett G, Baeten D.
Arthritis Rheumatol. 2015 May 4. doi: 10.1002/art.39183. [Epub ahead of print]

Different inflammatory joint diseases have distinct patterns of bone damage, but the molecular pathways determining each one remains poorly defined. This study investigates the wingless (Wnt)-signalling pathway, by analysing the expression of Dkk-1 (an inhibitor of the Wnt pathway) and its regulation by the pro-inflammatory cytokines TNF-α and IL-6 in SpA versus RA inflamed peripheral joints. Findings from the study show an inverse correlation of Dkk-1 with IL-6 in vivo and a differential...

Keywords: IL-6, Preclinical, MOA

Translated by: Bahtiyar Toz

ALX-0061 yüksek affiniteli anti-IL-6R nanoantikorun (nanobody) preklinik farmakolojisi Romatoid Artrit'de klinik gelişimini desteklemektedir

Van Roy M, Ververken C, Beirnaert E Hoefman S, Kolkman J Vierboom M, Breedveld E, 't Hart B, Poelmans S, Bontinck L, Hemeryck A, Jacobs S, Baumeister J, Ulrichts H.
Arthritis Res Ther. 2015 May 20;17(1):135. [Epub ahead of print]

Over the last decade, there has been a shift in treatment outcomes for RA; moving from symptom control to achieving remission. The TNF inhibitors have revolutionised treatment in this way, yet there is still a proportion of patients who fail to improve or reach remission. As such, new molecules for the treatment of RA are needed to be developed. This study investigates the in vitro and in vivo properties of ALX-0061, a bispecific Nanobody with a high affinity and potency for IL-6R. Positive ph...

Keywords: IL-6, Preclinical, PK-PD

Translated by: Bahtiyar Toz

May 15

Artritli hastalarda IL-17A ve TNF-α’ nın izole sinovyositin osteoblastik farklılaşması ve kemik eksplant üzerindeki farklı etkisi

Osta B, Roux JP, Lavocat F, Pierre M, Ndongo-Thiam N, Boivin G, Miossec P.
Frontiers in Immunology. 2015;6:151. doi:10.3389/fimmu.2015.00151

Inflammatory joint diseases such as RA and OA are characterised by bone and consequent joint destruction. The role of fibroblast-like synoviocytes (FLS) in the pathogenesis of such diseases is already established. This study compared the effects of TNF-α and IL-17A on osteogenic differentiation of isolated FLS and on whole bone explants from 3 RA and 10 OA patients. Results showed that isolated RA-FLS appeared more sensitive to the effects of TNF-α and IL-17A compared to OA-FLS. The...

Keywords: Cytokine Signalling, Preclinical

Translated by: Bahtiyar Toz

Aktif Romatoid Artrit hastalarında tofacitinibin ölçülmüş glomerüler filtrasyon oranına etkisinin değerlendirilmesi: Randomiza kontrollü çalışmalardan sonuçlar

Kremer JM, Kivitz AJ, Simon-Campos JA, Nasonov EL, Tony HP, Lee SK, Vlahos B, Hammond C, Bukowski J, Li H, Schulman SL, Raber S, Zuckerman A, Isaacs JD.
Arthritis Res Ther. 2015 Apr 6;17(1):95.

Mean increases from baseline in patient serum creatinine (SCr) levels have been observed in the clinical development programme for the JAK inhibitor tofacitinib. These increases predominantly occurred within the first three months, and reversed with tofacitinib withdrawal. This phase 1, randomised, placebo-controlled, parallel-group, 2-period study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib, relative to placebo, in 148 patients with active RA. Results sh...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Bahtiyar Toz

April 15

Süper güçlendiriciler(enhancer) T hücrelerinde hastalıkla-ilişkili düzenleyici devreleri tarif eder

Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ.
Nature. 2015 Feb 16. doi: 10.1038/nature14154. [Epub ahead of print]

Transcription machinery (proteins responsible for activating or ‘switching off’ genes) is not distributed in the genome in a symmetrical (or even) manner. Some parts of the genome, so called super-enhancers (SEs), accumulate an exceptionally high level of proteins relevant to the regulation of transcription (i.e. the machinery is concentrated in particular parts of the genome). In this paper, the investigators asked about the locale of these regions in the genome of T cells. Then th...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

March 15

Selektif Bir JAK1 İnhibitörü Olan Filgotinib’in (GLPG0634), Faz IIB Doz Seçimi’ni Destekleyen, Farmakokinetik Özellikleri ve Farmakokinetik/Farmakodinamik Modellemesi

Namour F, Diderichsen PM, Cox E, Vayssière B, Van der Aa A, Tasset C, Van't Klooster G.
Clin Pharmacokinet. 2015 Feb 14. [Epub ahead of print]

Filgotinib (GLPG0634) is a selective inhibitor of JAK1 currently in development for the treatment of RA and Crohn’s disease. This paper describes the pharmacokinetics of filgotinib and its active metabolite, as well as the PK/PD modelling to support dose selection for phase IIB. Two phase I, randomised, double-blind, placebo-controlled trials in healthy volunteers and one phase IIa proof-of-concept study in RA patients were used to evaluate single and multiple doses of filgotinib. Resul...

Keywords: JAK, Filgotinib, Preclinical, PK-PD

Translated by: Ege Sinan TORUN

İnflamatuar hastalıkların tedavisi için NLRP3 inflamazomunun küçük-moleküllü bir inhibitörü

Coll RC, Robertson AA, Chae JJ, et al.
Nat Med. 2015 Feb 16. doi: 10.1038/nm.3806. [Epub ahead of print]

A team of scientists at Trinity College Dublin and the University of Queensland Australia, led by Professor Luke O'Neill, have identified a key molecule that may result in the development of new anti-inflammatory therapies for diseases such as: cryopyrin-associated periodic syndrome (CAPS), multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. Professor O'Neill and his team have identified MCC950 as a potent, selective, small-molecule inhibitor of the ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

January 15

Romatoid Artritli Hastalarda Sağlıklı Gönüllülere Göre Anormal Lipid Profiline Neden Olan Potansiyel Mekanizmalar ve Bunların Tofacitinib Tarafından Tersine Çevrilmesi

Charles-Schoeman C, Fleischmann R, Davignon J, Schwartz H, Turner S, Beysen C, Milad M, Hellerstein M, Luo Z, Kaplan I, Riese R, Zuckerman A, McInnes IB.
Arthritis Rheumatol. 2015;67(3):616-25.

Active RA is associated with changes in both high- and low-density lipoprotein cholesterol as well as changes in the level and function of several HDL-associated proteins, yet the pathways and mechanisms involved with systemic inflammation altered lipid metabolism have not been determined. In addition, treatments for active RA are known to modify lipid metabolism, such as increasing circulating cholesterol levels. In the clinical development programme, a proportion of tofacitinib-treated patien...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

Bir Oral JAK 1/2 İnhibitörü Olan Baricitinib’in Sağlıklı Gönüllülerde Farmakokinetik, Farmakodinamik ve Güvenliği

Shi JG, Chen X, Lee F, Emm T, Scherle PA, Lo Y, Punwani N, Williams WV, Yeleswaram S.
Mod J Clin Pharmacol. 2014 Dec;54(12):1354-61. doi: 10.1002/jcph.354.

Current biologic therapies for RA, such as biologic cytokine inhibitors, which selectively target inflammatory molecules with an exquisite degree of specificity, are not clinically effective in all patients with rheumatoid arthritis. As such, there remains an unmet clinical need for more effective and better tolerated therapies. Baricitinib (LY3009104, also previously known as INCB028050) is a potent and selective small molecule inhibitor of JAK1/2, which play an important role in cytokine signa...

Keywords: JAK, Baricitinib, Preclinical, PK-PD

Translated by: Ege Sinan TORUN

IL-6 Hasar sonrası İntestinal Epitel Proliferasiyonu ve Tamirini Uyarır

Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS.
PLoS One. 2014 Dec 5;9(12):e114195. doi: 10.1371/journal.pone.0114195. eCollection 2014.

IL-6 is an inflammatory cytokine known to contribute to a number of autoimmune diseases such as RA. Therapies targeting the soluble IL-6 receptor have now become effective treatments for RA. However, one unforeseen, yet rare, potential complication of anti-IL-6 therapy is bowel perforation. Yet within the intestine, IL-6 protects intestinal epithelial cells from apoptosis during prolonged inflammation. The authors hypothesized that IL-6 may have beneficial properties in wound response/repair, s...

Keywords: IL-6, Preclinical, MOA

Translated by: Ege Sinan TORUN

December 14

Metotreksata yetersiz yanıt veren romatoid artritli hastalarda baricitinibin 24 haftadaki güvenlik ve etkinliği

Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus-Gort RK, Luchi ME, Rooney TP, Macias WL, Genovese MC.
Ann Rheum Dis. 2015;74(2):333–340

Recent innovations in the treatment of RA have focused on the use of small molecules to inhibit intracellular kinases such as the JAK family. Baricitinib (LY3009104, formerly INCB028050) is an orally administered, potent, selective and reversible inhibitor of JAK1 and JAK2, which has shown anti-inflammatory effects, as well as preservation of cartilage and bone, in preclinical rodent studies. This phase IIb study was designed to investigate multiple doses and dosing regimens of baricitinib, fo...

Keywords: JAK, Baricitinib, Clinical, Phase 2

Translated by: Ege Sinan TORUN

JAK-STAT yolunun romatoid artritteki aktivitesi: STAT3’ün konstitütif aktivasyonu interlökin 6 seviyeleri ile ilişkilidir.

Isomäki P, Junttila I, Vidqvist KL, Korpela M, Silvennoinen O.
Rheumatology (Oxford). 2014 Nov 17. pii: keu430. [Epub ahead of print]

Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT ...

Keywords: JAK, Preclinical, MOA

Translated by: Ege Sinan TORUN

JAK inhibitörü tofacitinib romatoid artritte sinovyal JAK1-STAT sinyalizasyonunu baskılar

Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, Shurmur R, Singhal AK, Wei N, Rosengren S, Kaplan I, Krishnaswami S, Luo Z, Bradley J, Firestein GS.
Ann Rheum Dis. 2014 Nov 14. pii: annrheumdis-2014-206028. doi: 10.1136/annrheumdis-2014-206028. [Epub ahead of print]

Targeting intracellular pathways such as JAK/STAT represents a novel approach to the treatment of RA. Tofacitinib is an oral JAK inhibitor, proven to be effective in the treatment of RA, yet the pathways affected by tofacitinib and the effects on gene expression in situ are unknown. In this study, Boyle et al. tested the hypothesis that tofacitinib targets cytokine signalling critical to the pathogenesis of rheumatoid synovitis by investigating tofacitinib effects on synovial pathobiology. A...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Ege Sinan TORUN

Romatoid artritte tedavi için terapötik fırsat olarak TNFα ve IL-17’nin kombine inhibisyonu: Yeni bir bispesifik antikorun geliştirilmesi ve nitelendirilmesi.

Fischer JA, Hueber AJ, Wilson S, Galm M, Baum W, Kitson C, Auer J, Lorenz S, Moelleken J, Bader M, Tissot AC, Tan SL, Seeber S, Schett G.
Arthritis Rheumatol. 2015;67(1):51–62

Single cytokine inhibition, e.g. TNFα or IL-6, has fundamentally improved the therapeutic armamentarium for the treatment of RA; yet clinically meaningful responses are achieved in only about half of RA patients treated. In addition, it is now well established that the pathogenesis of RA involves multiple mechanisms of cell activation and cell recruitment. These two factors have led to the emergence of the concept of dual specificity, sparking interest in the biologic arena, with a foc...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

September 14

Dalak tirozin kinaz inhibitörü fostamatinib’in aktif metaboliti dendritik hücrelerin CD4+ T hücrelerini «çalıştırma» (priming) kapasitesini ortadan kaldırır

Platt AM, Benson RA, McQueenie R, et al.
Rheumatology (Oxford). 2015;54(1):169–177

SYK is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors. While the clinical development of the first SYK inhibitor, fostamatinib, was stopped due to poor results in the phase 3 RA programme, there remain important questions of mechanism which may aid future developments of this target. In these murine studies, investigators sought to gain an understanding of how the active metabolite of fostamatinib, ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

August 14

Tofacitinib ile tedavi edilen aktif romatoid artritli hastalarda serum kreatinin düzeylerinde değişiklikler: klinik çalışmalardan elde edilen sonuçlar

Isaacs JD, Zuckerman A, Krishnaswami S, et al.
Arthritis Res Ther. 2014;16(4):R158

Despite preclinical and healthy volunteer studies of tofacitinib showing no evidence of nephrotoxicity, increases in mean serum creatinine levels have been observed in patients treated with the drug during the RA clinical development programme. This report explores the clinical significance of this change. Serum creatinine values and renal adverse event data were pooled from patients who received =1 dose of tofacitinib either with background DMARDs or as monotherapy in five Phase 3 studies a...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Ege Sinan TORUN

July 14

Nosiseptif duyu nöronları, interlökin-23 aracılı psöriasiform deri inflamasyonuna neden olur

Riol-Blanco L, Ordovas-Montanes J, Perro M, et al.
Nature. 2014;510(7503):157–161.

The abnormal activation of skin immune cells, such as dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, by IL-23 is known to provoke psoriasis-type inflammation. What is less well known is how peripheral nerves regulate cutaneous immune responses. In this study, IL-23-dependent psoriasis-like inflammation was induced in mice to help determine the precise molecular mechanism of neuroimmune communication in the skin. Finding...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Şafak Mirioğlu

June 14

Anti-inflamatuar genlerin p38 MAP kinaz ve MAP kinaz kinaz 6 tarafından farklı regülasyonu

Hammaker D, Boyle DL, Topolewski K et al.
Journal of Inflammation 2014, 11:14

Several p38α inhibitors have been developed and evaluated in RA. However, despite pre-clinical data showing promise, the compounds have been shown to have little therapeutic efficacy. Previous studies have suggested this may be a result of inhibitors blocking the role of p38 in limiting inflammation. Previous studies by the same authors have shown that the targeting of MKK3 or MKK 6, which are the upstream activators of p38, may be superior to p38 blockade as the anti-inflammatory eff...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

Alternatif p38 MAPKlar Kollajen ile Uyarılmış Artrit için Gereklidir

Criado G, Risco A, Alsina-Beauchamp D et al.
Arthritis and Rheumatology Vol66, No. 5, May2014 pp 1208-1217

MAPK family proteins are regulatory proteins, affecting processes such as synthesis and release of proinflammatory molecules which contribute to the pathogenesis of RA. In particular, the p38 MAPK protein family is central to proinflammatory cytokine production. There are four member of the p38 group; p38α, p38β, p38γ and p38δ. This study sought to evaluate p38γ and p38δ deficiency in mice CIA model. In p38γ-/- or p38&delt...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Şafak Mirioğlu

Büyüme Hormonu Reseptörü Tarafından JAK2 Protein Kinaz Aktivasyonunun Mekanizması

Brooks AJ, Dai W, O’Mara ML et al.
Science 344, 2014; doi: 10.1126/science.1249783

Class I cytokine receptors are key regulators of many processes within the body. The receptors use the JAK-STAT signalling pathway, the deregulation of which causes it to become an important pathway in oncogenesis. Despite this, the processes responsible for JAK2 activation by class I receptors remains elusive. Previous studies using growth hormone and its receptor have led to a model of receptor activation where hormone induced receptor dimerization resulted in close proximity of the receptor ...

Keywords: JAK, Preclinical, MOA

Translated by: Bahtiyar Toz

Protein kinaz TYK2'nin psödokinaz–kinaz alanlarının yapısı Janus kinaz (JAK) otoinhibisyonu için bir mekanizma ortaya çıkarmaktadır

Lupardus PJ, Ultsch M, Wallweber H et al.
Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]

The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood. This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation ...

Keywords: JAK, Preclinical, MOA

Translated by: Şafak Mirioğlu

Tirozin kinaz 2 tarafından tanınan interferon-α reseptörünün temel yapısı

Wallweber HJA, Tam C, Franke Y et al.
Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6

Janus kinases, JAKs, are essential in the mediation of cytokine and interferon signalling whilst also being crucial to body processes such as immune function, hematopoeises, metabolism and cellular growth. However, it is not known is how the four members of the JAK family interact with and are activated by over 30 cytokine receptors with near perfect affinity and specificity. Currently, there are no crystal structures available for any JAK bound to a cytokine receptor. This study sought address...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

May 14

AG490, farelerde JAK2-STAT3 inhibisyonu yaparak T reg ve Th17 hücrelerinin resiprok regülasyonu aracılığıyla Otoimmün Artriti baskılar

Park JS, Lee J, Lim MA et al.
J Immunol 2014; 192:4417-4424

In this study, Park et al sought to investigate the effects of the JAK2 inhibitor, AG490 in RA. Using murine CIA models, both preventative and therapeutic models were investigated. In the preventative model, CIA mice treated with AG490 showed a significantly lower incidence rate of arthritis and arthritic scores when compared to mice injected with vehicle. In the therapeutic model, as in the preventative, AG490 treated mice exhibited less severe arthritis. Through further experiments, it was de...

Keywords: JAK, Preclinical, MOA

Translated by: Bahtiyar Toz

Januz–aktive kinaz yolağının inhibisyonu,tümör nekroz faktör alfa ile indüklenen IL-18 biyoaktivitesini, kaspaz-1 inhibisyonu aracılığıyla, azaltır

Marotte H, Tsou PS, Fedorova T et al.
Arthritis Research and Therapy 2014,16:R102

IL-18, a member of the IL-1 family, has been shown to play an important role in immune response and is involved in the pathogenesis of RA. The study objective was to examine the role of the JAK pathway in modulating TNFa-induced-IL18 bioactivity by reducing caspase-1 function. Caspase-1 is the protease that cleaves pro-IL-18 to IL-18, thereby activating it. In testing it was noted that by blocking the JAK pathway significantly decreased caspase-1 transcription, expression and activity showing th...

Keywords: JAK, Preclinical, MOA

Translated by: Bahtiyar Toz

RA sinovyal doku eksplantlarında Btk inhibisyonu agonist ile indüklenen insan makrofaj aktivasyonunu ve inflamatuar gen ekspresyonunu baskılar

Hartkamp LM, Fine JS, van Es IE et al.
Ann Rheum Dis Published Online First 24 April 2014 doi:10.1136/annrheumdis-2013-204143

Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486. BTK was expressed at equivalent levels in both RA and PsA synovial tissu...

Keywords: BTK, Preclinical, MOA

Translated by: Bahtiyar Toz

Romatoid artrit ve eklem hasarı patogenezi ile ilişkili yeni bir medyatör: 14-3-3eta

Maksymowych WP, van der Heijde D, Allaart CF et al.
Arthritis Research and Therapy 2014, 16:R99

A major clinical imperative among rheumatologists is the ability to class patients into risk categories for radiographic progression. Indeed, identification of new independent biomarkers predictive of RA disease progression is a key target from OMERACT. This study by Maksymowych et al. sought to clarify the role of 14-3-3? in RA and whether it provided any clinically and/or serologically important prognostic information. First described as being elevated in RA in 2007, 14-3-3? has a strong corre...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

April 14

Romatoid Artrit Tedavisinde Kullanılan Janus Kinaz inhibitörü Tofasitinibin Serum Amiloid A ve IL-6 üzerine etkisi

Migita K, Izumi Y, Jiuchi Y et al.
Clinical and Experimental Immunology doi.10.1111/cei.12234

Tofacitinib is a JAK inhibitor currently approved for the treatment of RA in some parts of the world. In this paper, Migita et al tested the effects of tofacitinib on circulating serum amyloid A (SAA). SAA is a major acute-phase reactant in RA and studies have shown it may be a better marker for the assessment of inflammatory joint disease compared with C-reactive protein. SAA is induced by the binding of IL-6 and the activation of the JAK/STAT pathway, which is inhibited by tofacitinib. Results...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Bahtiyar Toz

Hipoksi ve STAT3 sinyalizasyonunun etkileşimleri romatoid artritte proinflamatuvar yolları düzenler

Gao W, McCormick J, Connolly M et al.
. ARD published online first 13 Feb 2014. Doi: 10.1136/annrheumdis-2013-204105

Hypoxia is a key driving force in joint inflammation, however little is known about the effect it can have on JAK/STAT signalling in rheumatoid arthritis. Due to the development of JAK inhibitors as therapeutics it is important to understand any links there may be. Previous studies have shown that HIF1a, a protein associated with hypoxia, facilitates the binding of STAT3 to haptoglobin promoter in HepG2 human hepatoma cells. HIF1a also requires interaction of Notch signalling pathways with STAT3...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Şafak Mirioğlu

March 14

Romatoid Artrit gelişme riski olan bireylerde sinovyumun özellikleri

de Hair MJH, van de Sande MGH, Ramwadhdoebe TH et al.
Arthritis and Rheumatology March 2014:66;513-522

This study expands on previous findings that synovial inflammation does not coincide with the appearance of rheumatoid arthritis. This was a markedly larger study compared to previous, with 55 individuals assessed. All 55 subjects were positive for IgM rheumatoid factor and/or anti-citrillinated protein antibody as well as possessing no physical evidence of arthritis. 15 of the individuals tested developed arthritis after a median time of 13 months. In these patients the presence of inflammatory...

Keywords: Preclinical, MOA

Translated by: Bahtiyar Toz

Romatoid Artrit Hastalarının Preklinik Dönemde Proinflamatuar Otoreaktif T Hücre Yanıtı

Aslam A, Nam J, Hunt L et al.
The Lancet, Volume 383, Page S22, 26 February 2014

Before the onset of clinically apparent disease, the pathogenesis of RA goes through a number of sequential phases. The presence of autoimmunity through RF and ACPAs can be detected up to 13 years before the onset of clinical synovitis. An important component of the immune system is Treg cells which limit damage caused by excessive immune activity. These cells have been found to be dysfunctional in RA. This study aimed to identify autoreactive T cells to a known RA-associated antigen and determi...

Keywords: Preclinical, MOA

Translated by: Bahtiyar Toz

Osteoartrit benzeri durumlarda TAK1 ve/veya JAK inhibisyonu insan mezenkimal kök hücrelerinin bozulmuş kıkırdak farklılaşmasını düzeltebilir

Van Beuningen HM, de Vries-van Melle ML, Vitters El et al.
Tissue Engineering Part A doi:10/1089/ten.TEA.2013.0553

As it is nonvascularized and noninnervated, articular cartilage has a limited capacity to repair which presents a major clinical problem. In order to circumvent this inability to repair, stem cells can be placed into the joint or stimulated within the bone marrow. However, as the cartilage requiring repair is often in diseased joints, the factors involved in the disease state are potentially non-beneficial to the chondrogenesis of mesenchymal stem cells. In this study van Beuningen et al. invest...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

February 14

Januz kinaz inhibitörü Tofasitinibin insanlarda farmakokinetik, metabolizma ve klirens mekanizması

Dowty ME, Lin J, Ryder TF et al.
DMD doi:10.1124/dmd.113.054940

The PK of tofacitinib has previously been described in several papers covering a range of diseases. This current study was used to better understand the PK, metabolism and clearance mechanisms of tofacitinib in healthy human subjects. Six subjects took a single 50mg dose of 14C-tofacitinib orally and consequently had urine, faeces and plasma collected. These were assayed for radioactivity and profiled for metabolites. Tofacitinib was found to be rapidly absorbed, with peak plasma concentration...

Keywords: JAK, Tofacitinib, Preclinical, PK-PD

Translated by: Bahtiyar Toz

Romatoid artritte tofacitinibin lenfositler üzerindeki etkileri: Etkinlikle ve enfeksiyöz yan etkilerle olan ilişki

Sonomoto K, Yamaoka K, Kubo S et al.
Rheumatology doi:10.1093/rheumatology/ket466

Due to its function as a JAK1/3 inhibitor, tofacitinib has effects on a wide ranging variety of cells. The authors of this paper have previously reported a suppression in cytokine production by CD4+ T lymphocytes caused by tofacitinib, while others have reported reduced chemokine production from fibroblast-like synoviocytes. The effects of tofacitinib on other cells however remain largely unknown. This study focused on tofacitinib’s effects on CD4+ T lymphocyte proliferation and on subsets...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Şafak Mirioğlu

January 14

IPI-145, PI3K-δ ve PI3K-γ inhibisyonu ile otoimmün ve inflamatuar hastalık modellerinde immün yanıt aktivitesini baskılar ve ortadan kaldırılmasını sağlar

Winkler DG, Faia KL, DiNitto JP et al.
Chemistry and Biology Nov 13 20, 1364-1374

Phosphoinositide-3 kinases (PI3K) are cell signalling proteins that act as a central node for relaying signals from cell surface receptors and downstream mediators. Specifically they phosphorylate phosphatidylinositol to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This acts a docking site for signalling proteins, leading to the activation of downstream effectors such as BTK. Therefore, inhibition of the PI3K-d and PI3K-? isoforms (PI3K-a and PI3K-ß demonstrated embryonic lethality in ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

Yeni Oral Küçük Molekül İnhibitörü RO9021 ın Dalak Tirozin Kinazı Selektif İnhibisyonuna Bağlı Doğuştan ve Adaptif İmmün Yanıt Üzerinde Ortaya Çıkan Etkiler: Otoimmün Hastalık Tedavisinde SYK Etkileri

Liao C, Hsu J, Kim Y et al.
Arthritis Research and Therapy 2013 15:R146

Spleen tyrosine kinase (SYK) has already been described as a potential therapeutic target for the treatment of autoimmune diseases. Previously the SYK inhibitor fostamatinib was in clinical development for the treatment of rheumatoid arthritis, but has since been suspended. However, investigation into SYK inhibition continues with RO2091, a novel ATP-competitive inhibitor of SYK with reasonable selectivity, potency and oral bioavailability which has been shown to suppress various innate and adap...

Keywords: Cytokine Signalling, Preclinical, Selectivity

Translated by: Bahtiyar Toz

STA-21, gelecek vadeden STAT3 inhibitörü olup Th17 ve Treg resiprok olarak düzenler, osteoklastogenezi inhibe eder ve otoimmün inflamasyonu iyileştirir

Park JS, Kwok SK, Lim MA et al.
Arthritis and Rheumatism doi: 10.1002/art.38305

STAT3 (signal transducer and activator of transcription 3) is the major transcription factor in the differentiation of Th17 cells, which along with IL-17 are significant in the development of RA. STA-21 is a new small molecule with significant inhibitory effects on STAT3, impeding DNA binding activity, dimerization and STAT3-dependent luciferase activity. While the effect of STA-21 in RA has not been fully determined, it has been hypothesised that STA-21 will suppress arthritis in animal models ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

Oral Btk inhibitörü İbrutinib Osteoklast Aracılı Kemik Kaybına Karşı Koruyucudur

Shinohara M, Chang BY, Buggy JJ et al.
Bone 2014;60:8-15

Ibrutinib is a first-in-class, orally available Btk (Bruton’s tyrosine kinase) inhibitor which has been shown to be effective in the treatment against certain types of leukemia and autoimmune disorders. Btk regulates the expression of genes involved in the differentiation and function of osteoclasts, and therefore inhibiting Btk suppresses osteoclastic bone resorption. Results from in vitro testing showed the suppressive effects on osteoclasts and murine models of RA showed ibrutinib treat...

Keywords: BTK, Preclinical, MOA

Translated by: Bahtiyar Toz

Romatoid Artrit de Januz Kinaz İnhibitörü Tofasitinibin Preklinikten Kliniğe Geçişi

Dowty M, Jesson MI, Ghosh S, et al.
J Pharmacol Exp Ther. 2013. DOI:10.1124/jpet.113.209304

Preclinical studies can provide insight into mechanisms of efficacy and optimal dosing regimens. In this study, Dowty et al. compare the pharmacokinetic / pharmacodynamic profiles of tofacitinib in a murine arthritis model and in patients with rheumatoid arthritis from tofacitinib clinical trials. The main driver of efficacy in both preclinical murine arthritis models and clinical RA was found to be inhibition of JAK1 heterodimer signalling, where total drug exposure (Cave) was a predictor of pr...

Keywords: JAK, Tofacitinib, Preclinical, PK-PD

Translated by: Bahtiyar Toz

October 13

Selektif JAK1 inhibitörü GLPG0634 nin inflamatuar hastalıkların tedavisinde preklinik özellikleri

Van Rompaey L, Galien R, van der Aar EM, et al.
Journal of Immunology 2013;191:3568–77

JAK inhibitors have been identified as having a critical role as therapeutic targets for autoimmune, inflammatory and oncological diseases. GLPG0634 was shown to inhibit JAK1/JAK2 but with a much greater effect on JAK1, a critical pathway in the signal transduction of many inflammatory cytokines. In rodent testing, GLPG0634 showed significant dose-dependent reduction in disease progression in collagen-induced arthritis models, with comparable efficacy to etanercept. An orally bioavailable treatm...

Keywords: JAK, Filgotinib, Preclinical

Translated by: Bahtiyar Toz

JAK inhibitörü Tofasitinib İnsan Monosit Kökenli Dendritik Hücrelerinin T hücre stimülator kapasitesini azaltır

Kubo S, Yamaoka K, Kondo M, et al.
Ann Rheum Dis 2013. doi: 10.1136/annrheumdis-2013-203756

The role of JAKs is highly important in lymphocyte differentiation, but their function in dendritic cells in unknown. In this study, the authors used tofacitinib, a JAK inhibitor, to assess the function of these kinases in dendritic cell activity. The results show that tofacitinib reduced the expression of CD80/CD86 by suppressing the activation of interferon regulatory factor (IRF)-7 and production of type 1 interferon (IFN), and also decreased T cell stimulatory capability. This suggests a nov...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Bahtiyar Toz, MD

June 13

Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050

Fridman JS, Scherle PA, Collins R, et al.
Journal of Immunology 2010; 184(9):5298-307

This preclinical characterisation study examined the efficacy and tolerability of the small molecule INCB028050 (now known as baricitinib), an orally bioavailable, selective Janus kinase (JAK) 1/JAK2 inhibitor, in rodent models of arthritis. The decision to investigate its effects of INCB028050 followed positive evidence for the related compound ruxolitinib, the JAK inhibitor tofacitinib and the IL-6 inhibitor tocilizumab in rheumatoid arthritis (RA). In this preclinical study, INCB028050 was sh...