Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor PF-06700841 Reveal Reduction of Skin Inflammation in Plaque Psoriasis

Page, Karen; Suárez‐Fariñas, Mayte; Suprun, Maria; Zhang, Weidong; Garcet, Sandra; Fuentes‐Duculan, Judilyn; Li, Xuan; Scaramozza, Matthew; Kieras, Elizabeth; Banfield, Christopher; Clark, James D.; Fensome, Andrew; Krueger, James G.; Peeva, Elena

doi:10.1016/j.jid.2019.11.027

Cited by 45 publications

(40 citation statements)

References 36 publications

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“…BMS-986165 is a selective Tyk2 inhibitor that have shown efficacy in a Phase II clinical trial for psoriasis treatment [80] (Table 1), and it is being studied in systemic lupus erythematosus, psoriatic arthritis, and inflammatory bowel diseases. Brepocitinib (PF-06700841) is a Tyk2/Jak1 inhibitor that is being tested in psoriasis [81] (Table 1). Interestingly, the efficacy of topical treatments with Jakinibs is being examined in clinical trials for treatment of dermatological disorders [82].…”

Section: Il-23 Proximal Signaling Cascade: Jaks/stats Modulementioning

confidence: 99%

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Pastor-Fernández

Mariblanca

Navarro

2020

Cells

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The interleukin 23 (IL-23) is a key pro-inflammatory cytokine in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators, such as IL-17, IL-22, granulocyte-macrophage colony-stimulating (GM-CSF), or the tumor necrosis factor (TNFα) by target populations, mainly Th17 and IL-17-secreting TCRγδ cells (Tγδ17). Due to their pivotal role in inflammatory diseases, IL-23 and its downstream effector molecules have emerged as attractive therapeutic targets, leading to the development of neutralizing antibodies against IL-23 and IL-17 that have shown efficacy in different inflammatory diseases. Despite the success of monoclonal antibodies, there are patients that show no response or partial response to these treatments. Thus, effective therapies for inflammatory diseases may require the combination of multiple immune-modulatory drugs to prevent disease progression and to improve quality of life. Alternative strategies aimed at inhibiting intracellular signaling cascades using small molecule inhibitors or interfering peptides have not been fully exploited in the context of IL-23-mediated diseases. In this review, we discuss the current knowledge about proximal signaling events triggered by IL-23 upon binding to its membrane receptor to bring to the spotlight new opportunities for therapeutic intervention in IL-23-mediated pathologies.

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Section: Il-23 Proximal Signaling Cascade: Jaks/stats Modulementioning

confidence: 99%

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Pastor-Fernández

Mariblanca

Navarro

2020

Cells

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“…Brepocitinib, which was formerly known as PF-06700841, is currently under investigation for several autoimmune indications [ 74 ]. It is known to directly inhibit TYK2-dependent IL-12, IL-23 signalling and JAK2 dependent signalling, which includes T-cells and keratinocytes [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

Repurposing of gastric cancer drugs against COVID-19

Sonkar

Doharey

Rathore

et al. 2021

Computers in Biology and Medicine

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Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global pandemic. Additionally, the SARS-CoV-2 infection in the patients of Gastric Cancer (GC; the third leading cause of death in the world) pose a great challenge for the health management of the patients. Since there have been uncertainties to develop a new drug against COVID-19, there is an urgent need for repurposing drugs that can target key proteins of both SARS-CoV-2 and GC. The SARS-CoV-2-RdRp protein contains the NiRAN domain, which is known to have kinase-like folds. A docking study of the FDA approved drugs against GC was performed using AutoDock 4.2 and Glide Schrodinger suite 2019 against SARS-CoV-2-RdRp protein. MMGBSA and MD simulation studies were performed to investigate the binding and stability of the inhibitors with the target protein. In this study, we have found 12 kinase inhibitors with high binding energies namely Baricitinib, Brepocitinib, Decernotinib, Fasudil, Filgotinib, GSK2606414, Peficitinib, Ruxolitinib, Tofacitinib, Upadacitinib, Pamapimod and Ibrutinib. These FDA approved drugs against GC can play a key role in the treatment of COVID-19 patients along with GC as comorbidity. We also hypothesize that JAK, ITK, Rho-associated kinases, FGFR2, FYN, PERK, TYK2, p38-MAPK and SYK kinases can be considered as key therapeutic targets in COVID-19 treatment. Taken altogether, we have proposed the SARS-CoV-2-RdRp as a potential therapeutic target through in-silico studies. However, further in-vitro and in-vivo studies are required for the validation of the proposed targets and drugs for the treatment of COVID-19 patients already suffering from GC.

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“…Additionally, JAK1 activity is positively correlated with Ki-67 expression. 40,41 Therefore, we investigated whether Anwulignan could inhibit Ki-67 expression in NSCLC tumour tissues. Results indicated that Anwulignan strongly reduced the Ki-67 expression ( Figure 6E).…”

Section: Discussionmentioning

confidence: 99%

Anwulignan is a novel JAK1 inhibitor that suppresses non‐small cell lung cancer growth

Xie

Wang

Shi

et al. 2021

J Cellular Molecular Medi

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Anwulignan is a monomer compound derived from Schisandra sphenanthera lignans. It has been reported to possess a spectrum of pharmacological activities, including anti‐bacterial, anti‐inflammatory, anticancer and hepatoprotective properties. However, its anticancer capacity and molecular mechanism(s) against non‐small cell lung cancer (NSCLC) have not been fully elucidated. Anwulignan significantly inhibited cell growth and increased G1‐phase cell cycle arrest in NSCLC cells. Anwulignan strongly attenuates the JAK1/STAT3 signalling pathway by directly targeting JAK1 protein kinase activity in vitro. The anticancer activity by Anwulignan is dependent upon the JAK1 protein expression. Remarkably, Anwulignan strongly inhibited tumour growth in vivo. In conclusion, Anwulignan is a novel JAK1 inhibitor that may have therapeutic implications for NSCLC management.

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Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor PF-06700841 Reveal Reduction of Skin Inflammation in Plaque Psoriasis

Cited by 45 publications

References 36 publications

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Repurposing of gastric cancer drugs against COVID-19

Anwulignan is a novel JAK1 inhibitor that suppresses non‐small cell lung cancer growth

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