-
Current Opinion in Hematology May 2024Cytokine-mediated signaling pathways, including JAK/STAT, PI3K/AKT, and Ras/MAPK pathways, play an important role in the process of erythropoiesis. These pathways are... (Review)
Review
PURPOSE OF REVIEW
Cytokine-mediated signaling pathways, including JAK/STAT, PI3K/AKT, and Ras/MAPK pathways, play an important role in the process of erythropoiesis. These pathways are involved in the survival, proliferation, and differentiation function of erythropoiesis.
RECENT FINDINGS
The JAK/STAT pathway controls erythroid progenitor differentiation, proliferation, and survival. The PI3K/AKT signaling cascade facilitates erythroid progenitor survival, proliferation, and final differentiation. During erythroid maturation, MAPK, triggered by EPO, suppresses myeloid genes, while PI3K is essential for differentiation. Pro-inflammatory cytokines activate signaling pathways that can alter erythropoiesis like EPOR-triggered signaling, including survival, differentiation, and proliferation.
SUMMARY
A comprehensive understanding of signaling networks is crucial for the formulation of treatment approaches for hematologic disorders. Further investigation is required to fully understand the mechanisms and interactions of these signaling pathways in erythropoiesis.
Topics: Humans; Signal Transduction; Erythropoiesis; Proto-Oncogene Proteins c-akt; Janus Kinases; Phosphatidylinositol 3-Kinases; STAT Transcription Factors; Cell Differentiation
PubMed: 38335037
DOI: 10.1097/MOH.0000000000000808 -
European Journal of Medicinal Chemistry Dec 2023Janus kinase (JAK) plays a crucial role in intracellular signaling pathways, particularly in cytokine-mediated signal transduction, making them attractive therapeutic... (Review)
Review
Janus kinase (JAK) plays a crucial role in intracellular signaling pathways, particularly in cytokine-mediated signal transduction, making them attractive therapeutic targets for a wide range of diseases, including autoimmune disorders, myeloproliferative neoplasms, and inflammatory conditions. The review provides a comprehensive overview of the development and therapeutic potential of small-molecule inhibitors targeting JAK family of proteins in various clinical trials. It also discusses the mechanisms of action, specificity, and selectivity of these inhibitors, shedding light on the challenges associated with achieving target selectivity while minimizing off-target effects. Moreover, the review offers insights into the clinical applications of JAK inhibitors, summarizing the ongoing clinical trials and the Food and Drug Administration (FDA)-approved JAK inhibitors currently available for various diseases. Overall, this review provides a thorough examination of the synthesis and clinical use of typical small-molecule JAK inhibitors in different clinical stages and offers a bright future for the development of novel small-molecule JAK inhibitors.
Topics: Humans; Janus Kinases; Janus Kinase Inhibitors; Myeloproliferative Disorders; Autoimmune Diseases; Signal Transduction
PubMed: 37793326
DOI: 10.1016/j.ejmech.2023.115848 -
Journal of Drugs in Dermatology : JDD Dec 2023Dysregulation of Janus kinase (JAK) pathways from uncontrolled cytokine signaling comprises the pathological basis for many complex inflammatory cutaneous disorders....
Dysregulation of Janus kinase (JAK) pathways from uncontrolled cytokine signaling comprises the pathological basis for many complex inflammatory cutaneous disorders. Oral JAK inhibitors, upadacitinib, tofacitinib, and baricitinib targeting JAK 1 and JAK 1/3, respectively, are currently US Food and Drug Administration (FDA)-approved for several rheumatic conditions. However, studies have shown that JAK-mediated signaling pathways are involved in many immune-related dermatologic conditions. As a result, for recalcitrant diseases, JAK inhibitors are potential alternative therapies due to their broad targeted inhibitory mechanisms. In this case series, we present the successful off-label treatment of 6 cases across dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease, which failed conventional therapies with upadacitinib or tofacitinib. In the 3 dermatomyositis cases, use of upadacitinib or tofacitinib demonstrated positive clinical outcomes, with no recurrent symptoms in cases where upadacitinib was used. In treatment-resistant hidradenitis suppurativa, upadacitinib demonstrated reduced systemic flares and moderate cutaneous symptom improvement. In the case of cutaneous Crohn’s disease, upadacitinib resulted in reduced cutaneous symptoms without new flares. Tofacitinib resulted in completed resolution of cutaneous symptoms in our patient’s case of cutaneous lupus erythematosus. JAK inhibitors upadacitinib and tofacitinib may be potential drug candidates in patients with treatment-resistant disease, especially in cases of inflammatory cutaneous conditions such as dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease. Further studies with larger sample sizes among these conditions are warranted to assess potential broader applicability of the positive results demonstrated in our patient cases. J Drugs Dermatol. 2023;22(12):1183-1190. doi:10.36849/JDD.7500.
Topics: Humans; Janus Kinase Inhibitors; Off-Label Use; Crohn Disease; Hidradenitis Suppurativa; Dermatomyositis; Dermatitis; Janus Kinases; Lupus Erythematosus, Cutaneous
PubMed: 38051858
DOI: 10.36849/JDD.7500 -
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 -
Immunological Medicine Sep 2023Recent studies have gradually elucidated the pathogenesis of inflammatory bowel disease; thus, the Janus kinase (JAK)-signal transducers and activators of transcription... (Review)
Review
Recent studies have gradually elucidated the pathogenesis of inflammatory bowel disease; thus, the Janus kinase (JAK)-signal transducers and activators of transcription pathway are strongly involved in the pathophysiology of inflammatory bowel disease. Generally, Janus kinase inhibitors are being used for the treatment of rheumatoid arthritis and other immunological diseases, with the therapeutic promising effects. Currently, in Japan, three Janus kinase inhibitors, namely tofacitinib, filgotinib, and upadacitinib, are available for the treatment of patients with active ulcerative colitis. Therefore, evaluating the efficacy and safety of each JAK inhibitor is essential for determining the role of JAK inhibitors in future therapeutic strategies for inflammatory bowel disease (IBD).
Topics: Humans; Janus Kinase Inhibitors; Colitis, Ulcerative; Inflammatory Bowel Diseases; Arthritis, Rheumatoid; Janus Kinases
PubMed: 37036140
DOI: 10.1080/25785826.2023.2195522 -
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 -
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 -
EBioMedicine Nov 2023JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders.... (Review)
Review
JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.
Topics: Humans; Janus Kinase Inhibitors; TYK2 Kinase; Autoimmune Diseases; Cytokines; Psoriasis; Janus Kinase 1
PubMed: 37863021
DOI: 10.1016/j.ebiom.2023.104840