c77118b1fa160d61291c43a80cad22eb pmc_9959504.pdf 507deb9f3ac2b5fc0a2964e63c70bb139799266f pmc_9959504.pdf b3f43c4b944a7f27ea84b1c92d73f16590ba7fe0836103e7dab3ed57d0eda4c1 pmc_9959504.pdf Title: Tyk2 Targeting in Immune-Mediated Inflammatory Diseases Subject: The Janus kinase (Jak)/signal transducer and activating protein (STAT) pathways mediate the intracellular signaling of cytokines in a wide spectrum of cellular processes. They participate in physiologic and inflammatory cascades and have become a major focus of research, yielding novel therapies for immune-mediated inflammatory diseases (IMID). Genetic linkage has related dysfunction of Tyrosine kinase 2 (Tyk2)—the first member of the Jak family that was described—to protection from psoriasis. Furthermore, Tyk2 dysfunction has been related to IMID prevention, without increasing the risk of serious infections; thus, Tyk2 inhibition has been established as a promising therapeutic target, with multiple Tyk2 inhibitors under development. Most of them are orthosteric inhibitors, impeding adenosine triphosphate (ATP) binding to the JH1 catalytic domain—which is highly conserved across tyrosine kinases—and are not completely selective. Deucravacitinib is an allosteric inhibitor that binds to the pseudokinase JH2 (regulatory) domain of Tyk2; this unique mechanism determines greater selectivity and a reduced risk of adverse events. In September 2022, deucravacitinib became the first Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis. A bright future can be expected for Tyk2 inhibitors, with newer drugs and more indications to come. Keywords: inflammatory diseases; psoriasis; treatment Author: Lluís Rusiñol and Luis Puig Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Feb 8 11:47:32 2023 CET ModDate: Wed Feb 8 11:50:33 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2638559 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- AKSWGP+URWPalladioL-Bold Type 1 Custom yes yes no 10 0 MJIQPY+URWPalladioL-Roma Type 1 Custom yes yes no 15 0 QTABSN+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 WLENKM+VnURWPalladioL-Bold Type 1 Custom yes yes no 23 0 CIQLLF+VnURWPalladioL Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 DORTIW+EURM10 Type 1 Builtin yes yes no 71 0 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CEST RepresentationInformation: pmc_9959504.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-09 02:14:05 CET Size: 2638559 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 571 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Jak-STAT Signaling and Inhibition Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Tyk2 Signaling and Pathogenetic Implications Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Tyk2 Pharmacologic Inhibition Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Children: Item: Title: Brepocitinib (PF-06700841) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Psoriasis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Alopecia Areata Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Atopic Dermatitis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: New Potential Therapeutic Indications Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Ropsacitinib (PF-06826647) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Phase 1 Clinical Trials Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Phase 2 Clinical Trials Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Deucravacitinib Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Children: Item: Title: Psoriasis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Psoriatic Arthritis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Other Therapeutic Indications Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: BMS-986202 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: SAR-20347 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Future Directions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Info: Title: Tyk2 Targeting in Immune-Mediated Inflammatory Diseases Author: Lluís Rusiñol and Luis Puig Subject: The Janus kinase (Jak)/signal transducer and activating protein (STAT) pathways mediate the intracellular signaling of cytokines in a wide spectrum of cellular processes. They participate in physiologic and inflammatory cascades and have become a major focus of research, yielding novel therapies for immune-mediated inflammatory diseases (IMID). Genetic linkage has related dysfunction of Tyrosine kinase 2 (Tyk2) the first member of the Jak family that was described to protection from psoriasis. Furthermore, Tyk2 dysfunction has been related to IMID prevention, without increasing the risk of serious infections; thus, Tyk2 inhibition has been established as a promising therapeutic target, with multiple Tyk2 inhibitors under development. Most of them are orthosteric inhibitors, impeding adenosine triphosphate (ATP) binding to the JH1 catalytic domain which is highly conserved across tyrosine kinases and are not completely selective. Deucravacitinib is an allosteric inhibitor that binds to the pseudokinase JH2 (regulatory) domain of Tyk2; this unique mechanism determines greater selectivity and a reduced risk of adverse events. In September 2022, deucravacitinib became the first Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis. A bright future can be expected for Tyk2 inhibitors, with newer drugs and more indications to come. 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