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Modeled human PK parameters of tofacitinib and estimation of JAK1 heterodimer or JAK2 homodimer IC 50 coverage Observed clinical variation in PK was within ∼30%.
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A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens which allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic/pharmacodynamic (PK/PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collagen-induced arthritis (mCIA) model...
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... In addition to this, it inhibits the transmission of signals through receptors for several cytokines, such as interleukins − 2, − 4, − 7, − 9, − 15, and − 21. The efficiency of this multimodal mechanism in autoimmune illnesses is attributed to its strategic modulation of numerous components of immune responses (Dowty et al., 2014). ...
Tofacitinib (TOF) is gaining recognition as a potent therapeutic agent for a variety of autoimmune disorders, including rheumatoid arthritis and psoriasis. Ensuring precise drug concentration control during treatment necessitates a rapid and sensitive detection method. This study introduces a novel electrochemical sensor employing a composite of nanodiamond (ND), copper aluminate spinel oxide (CuAl2O4), and iron (II, III) oxide (Fe3O4) as modified materials for efficient TOF detection. Extensive analyses using physicochemical and electrochemical techniques were carried out to characterize the morphological, structural, and electrochemical properties of the ND@CuAl2O4@Fe3O4 composite. Thereafter, various voltammetric methods were utilized to evaluate the electrochemical behavior of the ND@CuAl2O4@Fe3O4-modified glassy carbon electrode (GCE) concerning TOF determination. The fabricated electrode showcased superior performance in electrochemical TOF detection in a buffered solution (pH = 5), achieving a remarkably low detection limit of 7.8 nM and a linear response from 0.05 μM to 13.21 μM. Furthermore, applying the modified electrode as an electrochemical sensor exhibited exceptional selectivity, stability, and practicality in determining TOF in pharmaceutical and biological samples. Alongside the sensor development, this study conducted a thorough investigation using Density Functional Theory (DFT) for the geometry optimization of TOF and the TOF-ND complex. Consequently performed molecular docking studies using Janus Kinase 1 (JAK1) (PDB ID: 3EYG) and JAK3 (PDB ID: 3LXK) indicated higher interaction of the TOF-ND conjugate with the JAKs, reflected by binding energies of −12.9 kcal/mol and −11.7 kcal/mol for JAK1 and JAK3 respectively, compared to −7.0 kcal/mol and −6.9 kcal/mol for TOF alone. These findings illustrate the potential of the ND-based ND@CuAl2O4@Fe3O4 composite as a proficient sensing material for TOF detection and the merits of DFT in providing a detailed understanding of the interactions at play. This pioneering research holds promise for real-time TOF monitoring, which will advance personalized treatment strategies and improve therapeutic outcomes for patients with autoimmune disorders.
... However, natural killer cell counts decrease more prominently and dose-dependently. Treatment with tofacitinib was associated with dose-dependent increases in B cell counts, possibly due to JAK-3 inhibition and immunoglobulin levels slightly decrease (7). Tofacitinib rapidly decreased serum C-reactive protein (CRP) levels and stayed stable throughout the treatment. ...
... In a post hoc analysis of data from 21 tofacitinib clinical trials, the incidence rate of ILD was 0.18 per 100 patient-years after tofacitinib treatment [201]. Using a CIA mouse model, it has been reported that the administration of tofacitinib, a potent and selective inhibitor of JAK, significantly attenuates the development of arthritis [202][203][204]. ...
Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheu-matoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and eth-nicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast–myofibroblast transition, epithelial–mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the his-topathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.
... In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of serum from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations. [37]. Finally, cholesterol efflux was promoted for 6 h to either 10 µg/mL apolipoprotein A-I (apoA-I), 12.5 µg/mL native HDL (both from Merck, Darmstadt, Germany), or 2% v/v of normal human serum obtained from a pool of normolipidemic subjects. ...
The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations.
... It has been demonstrated that IL-6 and interferon gammainducible protein-10 can be inhibited rapidly. Other mechanistic assessments have shown that tofacitinib inhibition of cytokine receptor signaling in T cells can ultimately result in suppression of IL-12 as well as decreased production of inflammatory T helper 17 cells generated in response to IL-6 and IL-23 [24]. In addition, the in vivo effect of tofacitinib can also be evaluated in clinical trials where changes in disease activity parameters are measured. ...
Rheumatoid arthritis (RA) is an autoimmune, debilitating disorder with an inflammatory 14 condition that affects millions of patients worldwide, targeting the joints. Several unmet needs still 15 need to be addressed despite recent improvements in the management of RA. Although current RA 16 therapies can diminish inflammation and alleviate symptoms, many patients remain unresponsive 17 or experience flare-ups of their ailment. The present study aims to address these unmet needs 18 through in silico research, with a focus on the identification of novel potentially active molecules. 19 Therefore, a molecular docking analysis has been conducted using AutoDockTools 1.5.7 on Janus 20 kinase (JAK) inhibitors that are either approved for RA or in advanced phases of research. The bind-21 ing affinities of these small molecules against JAK1, JAK2, and JAK3, which are target proteins im-22 plicated in the pathophysiology of RA, have been assessed. Subsequent to identifying the ligands 23 with the highest affinity for these target proteins, a ligand-based virtual screening was performed 24 utilizing SwissSimilarity, starting with the chemical structures of the previously identified small 25 molecules. ZINC252492504 had the highest binding affinity (-9.0 kcal/mol) for JAK1, followed by 26 ZINC72147089 (-8.6 kcal/mol) for JAK2 and ZINC72135158 (-8.6 kcal/mol) for JAK3. Using Swis-27 sADME, an in silico pharmacokinetic evaluation showed that oral administration of the three small 28 molecules may be feasible. Based on the preliminary results of the present study, additional exten-29 sive research is required for the most promising candidates to be conducted so their efficacy and 30 safety profiles can be thoroughly characterized, and they can become medium-and long-term phar-31 macotherapeutic solutions for the treatment of RA. 32
... Tofacitinib (IC50 = 1.7-3.7 nM for JAK1, 1.8-4.1 nM for JAK2, and 0.75-1.6 nM for JAK3) was authorized to treat rheumatoid arthritis a year later [9][10][11][12][13]. Naphthoquinones are considerably favored structures in medicinal chemistry due to their biological activity and structural characteristics. ...
Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2′-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC50 = 9.57 and 18.10 μM) and HEL (IC50 = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. Flow cytometric analysis revealed that these two compounds induced apoptosis in TF1 cells in a time and dose-dependent manner. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.
... Given the historic use of the in vivo CIA model in drug discovery to successfully identify clinically relevant anti-arthritic drugs, which include anti-TNF biologics (Piquet et al., 1992;Bendele et al., 1999;Wang et al., 2013;Dowty et al., 2014) it was key for us to demonstrate efficacy with SAR441566 in this model. Encouragingly, the strong in vitro potency profile of SAR441566 was replicated in vivo with a dose dependent inhibition in signs of arthritis. ...
Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo . With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.
... Pellets were re-suspended in RPMI 1640 media including L-glutamine at a concentration of 5 × 10 6 cells/mL. Neutrophils were either left unstimulated or treated with therapeutically relevant concentrations of tofacitinib (200 ng/mL), baricitinib (200 ng/mL) [11,23] or pan-JAK inhibitor I (200 ng/mL) and incubated for 2 h. Deuterated DMSO was used as a vehicle control in all incubations at the same concentration as JAKi (v/v). ...
Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function can be modulated by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However, clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors have been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n = 6) and people with RA (n = 7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200 ng/mL) for 2 h. Metabolites were extracted, and 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models showed a divergent metabolic pattern in RA neutrophils compared to HC at 0 h (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p < 0.05). Bacterial killing was not impaired by JAK inhibitors, indicating that the effect of JAK inhibitors on neutrophils can inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.
... Pellets were re-suspended in RPMI 1640 media including L-glutamine at a concentration of 5 × 10 6 cells/mL. Neutrophils were either left unstimulated or treated with therapeutically relevant concentrations of tofacitinib (200 ng/mL), baricitinib (200 ng/mL) [11,23] or pan-JAK inhibitor I (200 ng/mL) and incubated for 2 h. Deuterated DMSO was used as a vehicle control in all incubations at the same concentration as JAKi (v/v). ...
Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function can be modulated by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors has been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n=6) and people with RA (n=7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200ng/mL) for 2h. Metabolites were extracted and ¹ H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models showed a divergent metabolic pattern in RA neutrophils compared to HC at 0h (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p<0.05). Bacterial killing was not impaired by JAK inhibitors, indicating the effect of JAK inhibitors on neutrophils can inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.
... In the treatment of rheumatoid arthritis, sulforaphane can also exert its effects by inhibiting the MAPK pathway as well as the NF-κB pathway (see the MAPK pathway section in the main text for the specific mechanism of this part). Subsequently, studies on other autoimmune diseases on the JAK-STAT pathway and the development of targets have gradually increased, and a large amount of experimental data as well as clinical evidence support the possibility of developing immunosuppressive agents on this pathway, and clinical trials for some other indications, such as graft-versus-host rejection, transplantation, asthma, and lupus (Dowty et al., 2014;Okiyama et al., 2014;Furumoto et al., 2017), have been successfully conducted and obtained satisfactory results. While the JAK-STAT pathway has been methodically studied, many discoveries have been made in other pathways, for example, sirolimus, which acts in the PI3K-AKT-mTOR pathway, has long been approved as an immunosuppressant for the prevention of immune rejection of organ transplantation; berberine and curcumin, which act in the Keap1/ARE-Nrf2 pathway, have also demonstrated their anti-inflammatory efficacy, providing a basis for future The development of immunosuppressive agents has laid the foundation for future development. ...
Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.
