Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in Japanese patients with moderate to severe plaque, erythrodermic, or generalized pustular psoriasis: Efficacy and safety results from an open-label, phase 3 trial.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in Japan for adult patients with plaque (PP), generalized pustular (GPP), and erythrodermic (EP) psoriasis who have had an inadequate response to conventional systemic therapies. This approval is based on results from the global phase 3 POETYK PSO-1 and PSO-2 trials in which deucravacitinib was associated with significantly improved efficacy outcomes compared with placebo in adults with moderate to severe plaque psoriasis, and results described here from POETYK PSO-4, an open-label, single-arm, phase 3 trial (NCT03924427), which evaluated the efficacy and safety of deucravacitinib 6 mg once daily in adult Japanese patients with PP, GPP, or EP. The coprimary endpoints were the proportion of patients achieving a ≥75% reduction from baseline in the Psoriasis Area and Severity Index (PASI 75) and a static Physician's Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1) with at least a two-point improvement from baseline at week 16. Nonresponder imputation was used for missing data. Efficacy responses, adverse events (AEs), and serious AEs (SAEs) were recorded for up to 52 weeks. Seventy-four patients were treated (PP, n = 63; GPP, n = 3; EP, n = 8). At week 16, 76.2%, 66.7%, and 37.5% of patients with PP, GPP, and EP, respectively, had achieved PASI 75, and 82.5%, 0.0%, and 50.0% had achieved sPGA 0/1. Responses were overall maintained through week 52. AEs occurred in 74.6% of patients with PP, 100% of patients with GPP, and 87.5% of patients with EP. The most common AEs were nasopharyngitis and acne. Rates of SAEs and discontinuations were low. There were no deaths. Deucravacitinib was effective and well tolerated in Japanese patients with moderate to severe PP and in a limited number of patients with GPP or EP.

Efficacy of tyrosine-kinase-2 and phosphodiesterase-4 inhibitors for scalp psoriasis: a systematic review and meta-analysis.

OBJECTIVES: Psoriasis of the scalp is challenging to manage. The only approved oral tyrosine kinase 2 and phosphodiesterase 4 inhibitors for psoriasis are deucravacitinib and apremilast. The aim of this study was to explore their efficacy for scalp psoriasis utilizing data from randomized controlled trials. METHODS: We searched Medline, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov up to August 4, 2023. To determine risk of bias, the revised Risk of Bias assessment tool 2.0 was used. Inverse variance random effects meta-analyses were executed. Heterogeneity was assessed utilizing Q and I2 statistics. Pre-determined outcomes included the proportion of participants with cleared scalp skin (Scalp Physician's Global Assessment [ScPGA] of 0/1), mean change in Psoriasis Scalp Severity Index (PSSI), and mean improvement in Dermatology Life Quality Index (DLQI). RESULTS: Ten RCTs fulfilled inclusion criteria. Both apremilast (RR = 2.41, 95% CI = 2.08-2.79, Tau2 = 0, I2 = 0) and deucravacitinib (RR = 3.86, 95% CI = 3.02-4.94, Tau2 = 0, I2 = 0) were more effective in inducing ScPGA of 0/1 at 16 weeks compared to placebo. Furthermore, deucravacitinib was more effective than apremilast (RR = 1.70, 95% CI = 1.44-2.00, Tau2 = 0, I2 = 0). An analysis could not be executed for the rest of the outcomes. CONCLUSIONS: Apremilast and deucravacitinib are effective for scalp psoriasis. Deucravacitinib may be more efficient in clearing the scalp.

Deucravacitinib: The First FDA-Approved Oral TYK2 Inhibitor for Moderate to Severe Plaque Psoriasis.

OBJECTIVE: The objective of this study was to review the safety and efficacy of deucravacitinib, a tyrosine kinase 2 (TYK2) inhibitor for moderate to severe plaque psoriasis. DATA SOURCES: Literature was reviewed from MEDLINE and Clinicaltrials.gov up to December 2022 using the terms "deucravacitinib" and "BMS-986165." STUDY SELECTION: Relevant articles in English relating to the pharmacodynamics, pharmacokinetics, efficacy, and safety of deucravacitinib were included. A total of 6 trial results were included. STUDY SELECTION AND DATA EXTRACTION: Deucravacitinib showed clinical efficacy across all the phase II and III clinical trials. Excluding the long-term extension study, there were 2248 subjects across all studies, with 63.2% of patients receiving deucravacitinib 6 mg daily. Of these subjects, the average proportion achieving a PASI 75 (a reduction of greater than 75% in the Psoriasis Area and Severity Index) at week 16 was 65.1%. Patients receiving deucravacitinib 6 mg once daily had a higher rate of achieving both PASI 75 response and a Static Physician's Global Assessment (sPGA) score of 0 or 1, compared with oral apremilast 30 mg twice daily. The safety profile of deucravacitinib includes mild adverse events (AEs), most commonly nasopharyngitis, with serious AEs reported ranging from 1.35% to 9.5%. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING MEDICATIONS: While many available therapies for moderate to severe plaque psoriasis rely on an injectable dosage form or extensive monitoring, deucravacitinib can potentially reduce patient medication-related burden. This review summarizes the efficacy and safety of oral deucravacitinib for the treatment of severe plaque psoriasis. CONCLUSION: Deucravacitinib shows a consistent efficacy and safety profile as the first oral TYK2 inhibitor approved for adult patients with moderate to severe plaque psoriasis who are eligible for systemic therapy or phototherapy treatment.

The correlation among Claudin-9, Tyrosine kinase-2, and Signal transducers and activators of transcription-3 expressions in non-functioning pituitary adenoma and invasiveness.

BACKGROUND: Deeper studies on the pathological mechanism associated with invasiveness of non-functioning pituitary adenoma (NFPA) is imperative to find better treatments. This research was preliminarily conducted to investigate the correlation between the expression of Claudin-9 (CLDN9), Tyrosine kinase-2 (TYK2), Signal transducers and activators of transcription-3 (STAT3) and invasiveness in NFPA to illustrate the pathological mechanism. METHODS: Clinical data and surgical specimens of 12 patients with NFPA were collected and divided into invasive and non-invasive NFPA groups, comprising six patients for each group. CLDN9, TYK2 and STAT3 transcription and expression levels in the NFPA tissues of the two groups were detected by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting (WB) and immunohistochemistry (IHC). The lentiviral plasmid transfection technique was used to develop a rat pituitary tumour GT1-1 cell line null control group (NC) and CLDN9-overexpressed experimental group (OE-CLDN9), and TYK2 and STAT3 transcription levels in the NC and OE-CLDN9 cell groups were detected using qRT-PCR. RESULTS: The CLDN9 and STAT3 expressions were significantly higher in invasive than in non-invasive NFPA tissues, whereas the TYK2 expression in invasive NFPA tissues was significantly lower than that in non-invasive NFPA (p < 0.001); The STAT3 upregulated (p < 0.001) and the TYK2 downregulated (p < 0.01) after the CLDN9 overexpression. CONCLUSION: Upregulated CLDN9 may increase the NFPA invasiveness through STAT3. In addition, low TYK2 expression might enhance the invasiveness in NFPA, which needs further studies to confirm. These results could provide a promising research leads for targeted treatment of NFPA.

Deucravacitinib, a selective tyrosine kinase 2 inhibitor, for the treatment of moderate-to-severe plaque psoriasis.

INTRODUCTION: Protein kinases play a crucial role in intracellular signaling pathways that lead to inflammation and cell proliferation. New understandings of the involvement of these metabolic pathways in the pathogenesis of psoriasis allowed the development of a new class of drugs. Unlike biologics, these compounds work by blocking intracellular targets involved in the immune response. AREAS COVERED: Deucravacitinib is an oral small-molecule inhibitor of TYK2 that binds the pseudokinase domain and locks the kinase in an inactive state by an allosteric mechanism, arresting TYK2-mediated signaling cascades and disabling the upregulation of proinflammatory genes implicated in psoriasis. The authors present the results of phase I-III clinical trials of deucravacitinib for the treatment of psoriasis. EXPERT OPINION: At week 16 about 56% of the patients treated with deucravacitinib achieved PASI75. No serious infections were reported, nor were thromboembolic events or laboratory abnormalities. Efficacy was reported to be persistent and safety profiles were shown to be consistent for up to 2 years. Deucravacitinib can potentially become a safe, effective, well-tolerated treatment for patients suffering from moderate-to-severe disease. Future studies and real-life experiences will be important to determine the exact role of this drug in the treatment of psoriasis.

Efficacy and Safety of the TYK2/JAK1 Inhibitor Brepocitinib for Active Psoriatic Arthritis: A Phase IIb Randomized Controlled Trial.

OBJECTIVE: Brepocitinib is a TYK2/JAK1 inhibitor in development for the treatment of several immunologic diseases. The efficacy and safety of oral brepocitinib were assessed in participants with moderately-to-severely active psoriatic arthritis (PsA) for up to 52 weeks. METHODS: In this placebo-controlled, dose-ranging, phase IIb study, participants were randomized to receive 10 mg, 30 mg, or 60 mg of brepocitinib once daily or placebo, advancing to 30 mg or 60 mg of brepocitinib once daily at week 16. The primary endpoint was the response rate according to the American College of Rheumatology criteria for 20% improvement (ACR20) in disease activity at week 16. Secondary endpoints included response rates according to the ACR50/ACR70 response criteria, 75% and 90% improvement in the Psoriasis Area and Severity Index (PASI75/PASI90) score, and minimal disease activity (MDA) at weeks 16 and 52. Adverse events were monitored throughout the study. RESULTS: Overall, 218 participants were randomized and treated. At week 16, the brepocitinib 30 mg and 60 mg once daily groups had significantly greater ACR20 response rates (66.7% [P = 0.0197] and 74.6% [P = 0.0006], respectively), versus the placebo group (43.3%), and significantly higher ACR50/ACR70, PASI75/PASI90, and MDA response rates. Response rates were maintained or improved through week 52. Adverse events were mostly mild/moderate; serious adverse events (15) in 12 participants (5.5%) included infections in 6 participants (2.8%) in the brepocitinib 30 mg and 60 mg once daily groups. No major adverse cardiovascular events or deaths occurred. CONCLUSION: Treatment with brepocitinib at dosages of 30 mg and 60 mg once daily was superior to placebo at reducing signs and symptoms of PsA. Brepocitinib was generally well tolerated throughout the 52-week study, with a safety profile consistent with those found in other brepocitinib clinical trials.

Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer.

Hyperactivated Janus kinase (JAK) signaling is an appreciated drug target in human cancers. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the efficacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades. Like JAKs, epigenetic modifiers of the histone deacetylase (HDAC) family regulate the growth and development of cells and are often dysregulated in cancer cells. The notion that inhibitors of histone deacetylases (HDACi) abrogate oncogenic JAK-dependent signaling cascades illustrates an intricate crosstalk between JAKs and HDACs. Here, we summarize how structurally divergent, broad-acting as well as isoenzyme-specific HDACi, hybrid fusion pharmacophores containing JAKi and HDACi, and proteolysis targeting chimeras for JAKs inactivate the four JAK proteins JAK1, JAK2, JAK3, and tyrosine kinase-2. These agents suppress aberrant JAK activity through specific transcription-dependent processes and mechanisms that alter the phosphorylation and stability of JAKs. Pharmacological inhibition of HDACs abrogates allosteric activation of JAKs, overcomes limitations of ATP-competitive type 1 and type 2 JAKi, and interacts favorably with JAKi. Since such findings were collected in cultured cells, experimental animals, and cancer patients, we condense preclinical and translational relevance. We also discuss how future research on acetylation-dependent mechanisms that regulate JAKs might allow the rational design of improved treatments for cancer patients. SIGNIFICANCE STATEMENT: Reversible lysine-ɛ-N acetylation and deacetylation cycles control phosphorylation-dependent Janus kinase-signal transducer and activator of transcription signaling. The intricate crosstalk between these fundamental molecular mechanisms provides opportunities for pharmacological intervention strategies with modern small molecule inhibitors. This could help patients suffering from cancer.

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway.

Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.

Deucravacitinib, a Tyrosine Kinase 2 Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE). METHODS: Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI-4) response at week 32. Secondary outcomes assessed at week 48 included SRI-4, British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts. RESULTS: At week 32, the percentage of patients achieving SRI-4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95% CI) 1.5, 5.1]; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 [95% CI 1.0, 3.4]; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 [95% CI 0.8, 2.9]; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI-50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported. CONCLUSION: Deucravacitinib treatment elicited higher response rates for SRI-4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE.

Selective TYK2 Inhibition in the Treatment of Moderate to Severe Chronic Plaque Psoriasis

Moderate to severe chronic plaque psoriasis may be difficult to control using current therapies, which has led to development of a novel class of therapy, selective tyrosine kinase 2 (TYK2) inhibitors, to address this unmet need. Oral deucravacitinib is a first-inclass selective TYK2 inhibitor, which has shown efficacy in moderate to severe chronic plaque psoriasis from two phase III pivotal trials (POETYK PSO-1 and PSO-2), whereby response rates were significantly higher with deucravacitinib vs. placebo or apremilast for Psoriasis Area Severity Index (PASI) 75 and static Physician's Global Assessment (sPGA) 0/1. Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast. Although deucravacitinib is a type of Janus kinase (JAK) inhibitor, it only blocks specific cytokine-driven responses, potentially reducing off-target effects more commonly associated with other JAK inhibitors on the market. Incidence rates of serious adverse events, such as serious infections, malignancies, thrombosis, cardiovascular events, creatinine kinase elevation, hematologic changes, and lipid profile abnormalities were absent or low.

Nonreceptor Tyrosine Kinase c-Abl-Mediated PHB2 Phosphorylation Aggravates Mitophagy Disorder in Parkinson's Disease Model.

Mitophagy and oxidative stress play important roles in Parkinson's disease (PD). Dysregulated mitophagy exacerbates mitochondrial oxidative damage; however, the regulatory mechanism of mitophagy is unclear. Here, we provide a potential mechanistic link between c-Abl, a nonreceptor tyrosine kinase, and mitophagy in PD progression. We found that c-Abl activation reduces the interaction of prohibitin 2 (PHB2) and microtubule-associated protein 1 light chain 3 (LC3) and decreases the expressive level of antioxidative stress proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), NADPH quinone oxidoreductase-1 (NQO-1), and the antioxidant enzyme heme oxygenase-1 (HO-1) in 1-methyl-4-phenylpyridinium- (MPP+-) lesioned SH-SY5Y cells. Importantly, we found that MPP+ can increase the expression of phosphorylated proteins at the tyrosine site of PHB2 and the interaction of c-Abl with PHB2. We showed for the first time that PHB2 by changing tyrosine (Y) to aspartate (D) at site 121 resulted in impaired binding of PHB2 and LC3 in vitro. Moreover, silencing of PHB2 can decrease the interaction of PHB2 and LC3 and exacerbate the loss of dopaminergic neurons. We also found that STI 571, a c-Abl family kinase inhibitor, can decrease dopaminergic neuron damage and ameliorate MPTP-induced behavioral deficits in PD mice. Taken together, our findings highlight a novel molecular mechanism for aberrant PHB2 phosphorylation as an inhibitor of c-Abl activity and suggest that c-Abl and PHB2 are potential therapeutic targets for the treatment of individuals with PD. However, these results need to be further validated in PHB2 Y121D mice.

Isorhamnetin Attenuated the Release of Interleukin-6 from ß-Amyloid-Activated Microglia and Mitigated Interleukin-6-Mediated Neurotoxicity.

Alzheimer's disease (AD), characterized by the abnormal accumulation of ß-amyloid (Aß), is the most prevalent type of dementia, and it is associated with progressive cognitive decline and memory loss. Aß accumulation activates microglia, which secrete proinflammatory factors associated with Aß clearance impairment and cause neurotoxicity, generating a vicious cycle among Aß accumulation, activated microglia, and proinflammatory factors. Blocking this cycle can be a therapeutic strategy for AD. Using Aß-activated HMC3 microglial cells, we observed that isorhamnetin, a main constituent of Oenanthe javanica, reduced the Aß-triggered secretion of interleukin- (IL-) 6 and downregulated the expression levels of the microglial activation markers ionized calcium binding adaptor molecule 1 (IBA1) and CD11b and the inflammatory marker nuclear factor-κB (NF-κB). Treatment of the SH-SY5Y-derived neuronal cells with the Aß-activated HMC3-conditioned medium (HMC3-conditioned medium) or IL-6 increased reactive oxygen species production, upregulated cleaved caspase 3 expression, and reduced neurite outgrowth, whereas treatment with isorhamnetin counteracted these neurodegenerative presentations. In the SH-SY5Y-derived neuronal cells, IL-6 upregulated the phosphorylation of tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription 1 (STAT1), whereas isorhamnetin normalized this abnormal phosphorylation. Overexpression of TYK2 attenuated the neuroprotective effect of isorhamnetin on IL-6-induced neurotoxicity. Our findings demonstrate that isorhamnetin exerts its neuroprotective effect by mediating the neuroinflammatory IL-6/TYK2 signaling pathway, suggesting its potential for treating AD.

Deucravacitinib for the Treatment of Psoriatic Disease.

Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is responsible for mediating immune signalling of IL-12, IL-23 and type I interferons, without interfering with other critical systemic functions as other JAK proteins do. This article aims to review the current knowledge on deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a low risk of off-target effects. After good efficacy and safety results in a phase II, placebo-controlled trial, two phase III, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast-an active comparator. POETYK PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. In POETYK PSO-1, these results improved until week 24 and were maintained through week 52, with over 65% of patients achieving PASI75 at this point. A reduction in signs and symptoms was also reported by patients, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities, which are a concern among other JAK inhibitors. Persistent efficacy and consistent safety profiles were reported for up to 2 years. Despite advances in the treatment of psoriasis, namely among biologic agents, an oral, effective and safe new drug can bring several advantages to prescribers and patients. Further investigation is required to understand where to place deucravacitinib among current psoriasis treatment options.

Association of germline TYK2 variation with lung cancer and non-Hodgkin lymphoma risk.

Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate-to-severe plaque psoriasis. It is unclear whether recent safety concerns (ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss-of-function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non-Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta-analysis of 29 266 cases and 56 450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non-Hodgkin lymphoma risk were obtained from a GWAS meta-analysis of 8489 cases and 374 506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.09-1.23, P = 2.29 × 10-6 ) and non-Hodgkin lymphoma (OR 1.18, 95% CI 1.05-1.33, P = 5.25 × 10-3 ). Our analyses using an established partial loss-of-function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non-Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development.

Pirfenidone attenuates cardiac hypertrophy against isoproterenol by inhibiting activation of the janus tyrosine kinase-2/signal transducer and activator of transcription 3 (JAK-2/STAT3) signaling pathway.

Cardiovascular risk factors have attracted increasing attention in recent years with the acceleration of population aging, amongst which cardiac hypertrophy is the initiating link to heart failure. Pirfenidone is a promising agent for the treatment of idiopathic pulmonary fibrosis and has recently proven to exert inhibitory effects on the inflammatory response. This study proposes to explore the potential pharmacological action of Pirfenidone in treating cardiac hypertrophy in a rodent model. Four groups of mice were used in the present study: the control, ISO (5 mg/kg/day) for 7 days, Pirfenidone (200 mg/kg/day) for 14 days, and Spironolactone (SPI) (200 mg/kg/day) for 14 days groups. Increased heart weight index, left ventricle (LV) weight index, LV wall thickness, declined LV volume, and elevated serum levels of CK-MB, AST, and LDH were observed in ISO-challenged mice, all of which were dramatically reversed by the administration of Pirfenidone or SPI. Furthermore, an elevated cross-sectional area of cardiomyocytes in the wheat germ agglutinin (WGA) staining of heart cross-sections, upregulated atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), ß Myosin Heavy Chain (ß-MHC), and excessively released tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in cardiac tissues were observed in the ISO group but greatly alleviated by Pirfenidone or SPI. Lastly, the promoted expression levels of p-JAK-2/JAK-2 and p-STAT3/STAT-3 in the cardiac tissues of ISO-challenged mice were significantly repressed by Pirfenidone or SPI. Collectively, our data reveals a therapeutic property of Pirfenidone on ISO-induced cardiac hypertrophy in mice.

Selective tyrosine kinase 2 inhibitors in inflammatory bowel disease.

Recent significant advances have been made in the treatment of chronic inflammatory diseases with initiation of the era of biologics. However, an unmet medical need still exists for novel targeted therapies. Compared with biologics, Janus kinase inhibitors (JAKis) are a new drug class of orally administered small molecules that have been shown to efficiently modulate complex cytokine-driven inflammation in preclinical models and human studies. Unfortunately, serious adverse effects have been reported with the first introduced pan-JAKi, tofacitinib. Here, we review tyrosine kinase 2 (TYK2) signaling in the pathophysiology of inflammatory bowel disease (IBD), examine mechanisms of action of selective TYK2 inhibitors (TYK2is), and discuss the potential for these inhibitors in efforts to balance benefits and harms.

[TKI 2.0 - changes in the medical treatment of renal cell carcinoma]. / TKI 2.0 ­ Wandel in der medikamentösen Therapie des Nierenzellkarzinoms.

Only for renal cell carcinoma (RCC) in a local stage curative treatment option by surgical resection exists. For metastatic disease the 5­year survival rate decreases radically. A factor that contributes to this is the low sensibility to radiation and chemotherapeutics. Since the approval of the tyrosine kinase inhibitors in 2006 effective drugs for the treatment of mRCC is available. The specific inhibition of the vascular-endothelial-growth (VEGF)-receptor and the "mammalian Target of Rapamycin" (mTOR) leads to a prolongation of the progression-free survival as well as the overall survival rate. For a long time, the current target therapy with TKI appeared to be exhausted, but since recently research has gone a step further. Thus, Cabozantinib and Lenvatinib in the combination with Everolimus have been approved for second-line therapy in mRCC. For the first time a clinical study demonstrated positive results for an adjuvant treatment with sunitinib in patients with a high-risk RCC. Furthermore, in april 2016 the immune checkpoint inhibitor Nivolumab was approved for second-line therapy in mRCC in Germany. The following report examines briefly the current therapeutic recommendations, new findings and drug approvals and ongoing clinical trials.