-
Biomolecules Nov 2023Colorectal cancer is a known complication of chronic inflammation of the colon ("colitis-associated colon cancer"). Inflammatory bowel disease (IBD) is a chronic... (Review)
Review
Colorectal cancer is a known complication of chronic inflammation of the colon ("colitis-associated colon cancer"). Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Patients with IBD are at increased risk of colon cancer compared to the general population. Kinase signaling pathways play critical roles in both the inflammation and regulating cellular processes such as proliferation and survival that contribute to cancer development. Here we review the interplay of kinase signaling pathways (mitogen-activated protein kinases, cyclin-dependent kinases, autophagy-activated kinases, JAK-STAT, and other kinases) and their effects on colitis-associated colon cancer. We also discuss the role of JAK-STAT signaling in the pathogenesis of IBD and the therapeutic landscape of JAK inhibitors for the treatment of IBD.
Topics: Humans; Colitis-Associated Neoplasms; Inflammatory Bowel Diseases; Janus Kinases; Inflammation
PubMed: 38002302
DOI: 10.3390/biom13111620 -
Blood Advances Oct 2023In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The...
In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Pacritinib's inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P < .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition.
Topics: Humans; Primary Myelofibrosis; Hepcidins; Janus Kinase 2; Anemia; Janus Kinase Inhibitors; Activin Receptors, Type I
PubMed: 37552106
DOI: 10.1182/bloodadvances.2023010151 -
Gastroenterology & Hepatology Dec 2023Ulcerative colitis and Crohn's disease are chronic, progressive inflammatory bowel diseases (IBDs) and are without a known cure. Janus kinase (JAK) is a family of...
Ulcerative colitis and Crohn's disease are chronic, progressive inflammatory bowel diseases (IBDs) and are without a known cure. Janus kinase (JAK) is a family of cytosolic tyrosine kinases that mediate signal transduction in response to extracellular stimuli. Abrogating the proinflammatory cytokine signaling cascades using JAK inhibitors (jakinibs) has been shown to be highly effective in the treatment of numerous inflammatory diseases, including IBD. Jakinibs currently licensed for moderate-to-severe IBD include the first-generation, nonselective tofacitinib and the second-generation JAK1-selective inhibitors filgotinib (licensed outside of the United States) and upadacitinib; several other jakinibs in the therapeutic pipeline are in various stages of clinical development. The jakinib class of small-molecule drugs share numerous commonalities such as their oral administration, nonimmunogenicity, short half-life, rapid onset of action, and the same class-wide regulatory restrictions owing to safety concerns. However, jakinibs differ on several fronts, translating into important clinical practice points for health care providers managing IBD patients. This article provides an overview of the jakinib class in IBD, examines how each drug differs in terms of pharmacology as well as efficacy and safety, and offers perspectives on challenges that remain and future opportunities.
PubMed: 38404416
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... Nov 2023Tyrosine kinase 2 (TYK2) as a member of Janus kinase (JAK) family, mainly mediates the signaling of type I interferons (IFN), interleukin-12 (IL-12) and interleukin-23...
Tyrosine kinase 2 (TYK2) as a member of Janus kinase (JAK) family, mainly mediates the signaling of type I interferons (IFN), interleukin-12 (IL-12) and interleukin-23 (IL-23), which has become an attractive target for treatment of immune and inflammatory diseases. However, the development of selective TYK2 inhibitors is challenging due to the high homology of the catalytic kinase domain among the JAK family members. Here, we report a novel and potent allosteric inhibitor, WD-890, which binds to the pseudokinase domain of TYK2 with high selectivity and inhibits its function. We accomplished a series of preclinical studies to demonstrate the therapeutic efficacy of WD-890 in four animal models: systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD). The pharmacokinetic and toxicology results further indicate that WD-890 has favorable absorption, distribution, metabolism, and excretion (ADME) properties and tolerable toxicity. In conclusion, our study shows that WD-890 could be a promising oral TYK2 inhibitor for future treatment of autoimmune diseases.
Topics: Animals; TYK2 Kinase; Arthritis, Psoriatic; Autoimmune Diseases; Janus Kinases; Interleukin-12
PubMed: 37778274
DOI: 10.1016/j.biopha.2023.115611 -
Circulation Journal : Official Journal... Dec 2023Takayasu arteritis (TAK) is a rare disease characterized by inflammation of large blood vessels, which results in vascular stenosis, occlusion, and aneurysm formation....
Takayasu arteritis (TAK) is a rare disease characterized by inflammation of large blood vessels, which results in vascular stenosis, occlusion, and aneurysm formation. The principal treatment has been glucocorticoids, but the recent emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), represented by tocilizumab (TCZ), has significantly changed the treatment landscape. Both cardiologists and cardiovascular surgeons will encounter patients receiving these drugs who require catheterization, other invasive procedures, or surgery. Several bDMARDs have shown promise against TAK in clinical studies and their use is expected to increase in the future. Janus kinase inhibitors may also be effective. Here, we review the evidence supporting the use of TCZ and other immunosuppressants in TAK and provides an update on their status as well as the relevant guidelines.
PubMed: 38123294
DOI: 10.1253/circj.CJ-23-0780 -
Vascular Health and Risk Management 2023Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory... (Review)
Review
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV.
Topics: Humans; Polycythemia Vera; Cardiovascular Diseases; Quality of Life; Janus Kinase 2; Risk Factors; Thrombosis; Heart Disease Risk Factors
PubMed: 38025519
DOI: 10.2147/VHRM.S429995 -
Science Advances Dec 2023Steroids are the standard treatment for allergic airway inflammation in asthma, but steroid-refractory asthma poses a challenge. Group 2 innate lymphoid cells (ILC2s),...
Steroids are the standard treatment for allergic airway inflammation in asthma, but steroid-refractory asthma poses a challenge. Group 2 innate lymphoid cells (ILC2s), such as T helper 2 (T2) cells, produce key asthma-related type 2 cytokines. Recent insights from mouse and human studies indicate a potential connection between ILC2s and steroid-resistant asthma. Here, we highlight that lung ILC2s, rather than T2 cells, can develop steroid resistance, allowing them to persist and maintain their disease-driving activity even during steroid treatment. The emergence of multipotent IL-5IL-13IL-17A ILC2s is associated with steroid-resistant ILC2s. The Janus kinase 3 (JAK3)/signal transducer and activator of transcription (STAT) 3, 5, and 6 pathways contribute to the acquisition of steroid-resistant ILC2s. The JAK3 inhibitor reduces ILC2 survival, proliferation, and cytokine production in vitro and ameliorates ILC2-driven -induced asthma. Furthermore, combining a JAK3 inhibitor with steroids results in the inhibition of steroid-resistant asthma. These findings suggest a potential therapeutic approach for addressing this challenging condition in chronic asthma.
Topics: Humans; Animals; Mice; Immunity, Innate; Janus Kinase Inhibitors; Lymphocytes; Asthma; Cytokines; Inflammation; Steroids; Janus Kinase 3
PubMed: 38117887
DOI: 10.1126/sciadv.adi3770 -
Investigative Ophthalmology & Visual... Sep 2023This study aimed to elucidate the impact of upadacitinib, a Janus kinase 1 (JAK1)-specific inhibitor, on experimental autoimmune uveitis (EAU) and explore its underlying...
PURPOSE
This study aimed to elucidate the impact of upadacitinib, a Janus kinase 1 (JAK1)-specific inhibitor, on experimental autoimmune uveitis (EAU) and explore its underlying mechanisms.
METHODS
We utilized single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to investigate the JAK/signal transducer and activator of transcription (STAT) pathway in peripheral blood mononuclear cells (PBMCs) of 12 patients with Vogt-Koyanagi-Harada (VKH) disease and cervical draining lymph node (CDLN) cells of EAU. After treating EAU with upadacitinib, we analyzed immune cell gene expression and cell-cell communication by integrating scRNA data. Additionally, we applied flow cytometry and western blot to analyze the CDLN cells.
RESULTS
The JAK/STAT pathway was found to be upregulated in patients with VKH disease and EAU. Upadacitinib effectively alleviated EAU symptoms, reduced JAK1 protein expression, and suppressed pathogenic CD4 T cell (CD4TC) proliferation and pathogenicity while promoting Treg proliferation. The inhibition of pathogenic CD4TCs by upadacitinib was observed in both flow cytometry and scRNA data. Additionally, upadacitinib was found to rescue the interferon-stimulated gene 15 (ISG15)+ CD4TCs and CD8 T and B cell ratios and reduce expression of inflammatory-related genes. Upadacitinib demonstrated the ability to inhibit abnormally activated cell-cell communication, particularly the CXCR4-mediated migration pathway, which has been implicated in EAU pathogenesis. CXCR4 inhibitors showed promising therapeutic effects in EAU.
CONCLUSIONS
Our findings indicate that the JAK1-mediated signaling pathway is significantly upregulated in uveitis, and upadacitinib exhibits therapeutic efficacy against EAU. Furthermore, targeting the CXCR4-mediated migration pathway could be a promising therapeutic strategy.
Topics: Humans; Signal Transduction; Janus Kinases; Leukocytes, Mononuclear; STAT Transcription Factors; Uveitis; Uveomeningoencephalitic Syndrome; Single-Cell Analysis
PubMed: 37713206
DOI: 10.1167/iovs.64.12.28 -
Haematologica Feb 2024
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Nitriles; Janus Kinase 2; Benzamides; Pyrazoles
PubMed: 37259556
DOI: 10.3324/haematol.2023.283106