{"id":77,"date":"2024-02-05T17:34:26","date_gmt":"2024-02-05T09:34:26","guid":{"rendered":"https:\/\/www.fulmz.com\/news\/?p=77"},"modified":"2024-02-19T13:34:42","modified_gmt":"2024-02-19T05:34:42","slug":"preclinical-profiles-of-fz007-119-a-highly-potent-and-selective-tyk2-inhibitor-for-the-treatment-of-immune-mediated-inflammatory-diseases","status":"publish","type":"post","link":"https:\/\/www.fulmz.com\/news\/preclinical-profiles-of-fz007-119-a-highly-potent-and-selective-tyk2-inhibitor-for-the-treatment-of-immune-mediated-inflammatory-diseases\/","title":{"rendered":"Preclinical Profiles of FZ007-119, a Highly Potent and Selective Tyk2 Inhibitor, for the Treatment of Immune Mediated Inflammatory Diseases"},"content":{"rendered":"\n<p><em>Monday, November 13, 2023<\/em><\/p>\n\n\n\n<p><strong>Background\/Purpose:<\/strong>&nbsp;Tyrosine Kinase 2 (TYK2) is a signaling protein within the Janus kinase (JAK) family. It plays a crucial role in transmitting signals from pro-inflammatory cytokines like IL-23, IL-12, and Type I IFN, which contribute to Immune Mediated Inflammatory Diseases (IMIDs). Here we report a novel oral TYK2 inhibitor called FZ007-119, unlike traditional kinase inhibitors that target the catalytic domain, which acts through an allosteric mechanism by binding to the pseudokinase Janus homology 2 regulatory domain (JH2) of the TYK2 enzyme. This specific mode of action allows selective inhibition of TYK2 without affecting other kinases. Current preclinical studies indicate that FZ007-119 shows promise as a treatment for IMIDs while avoiding the side effects associated with non-selective JAK inhibitors.<\/p>\n\n\n\n<p><strong>Methods:<\/strong>&nbsp;We employ our AI-driven structure-based drug design tool to discover selective Tyk2 inhibitors. These compounds are characterized for their drug-like properties, potency, selectivity in both enzyme and cell-based assays, DMPK in vitro and in vivo\uff0cas well as in mouse models of psoriasis and atopic dermatitis.<\/p>\n\n\n\n<p><strong>Results:<\/strong>&nbsp;FZ007-119 exhibits high potency and specificity for binding to TYK2 JH2 (IC50=0.19nM). It does not show activity against JH1 (protein kinase domain) of JAK1, JAK2, JAK3 and TYK2 (IC50 &gt;10\u03bcM) based on HTRF kinase assays. Cell-based assays on human PBMCs demonstrate that FZ007-119 is a potent inhibitor of IFN\u03b1 stimulated TYK2 dependent signaling ( IC50 = 12.2 nM) and is selective over GM-CSF induced JAK2 dependent signaling (IC50\uff1e30\u03bcM) and IL-2 induced JAK1\/3 dependent signaling (IC50\uff1e30\u03bcM). FZ007-119 exhibits excellent selectivity against a panel of 207 kinases (less than 50% inhibition at 1\u03bcM) and a safety panel of 90 targets (less than 50% inhibition at 10\u03bcM). FZ007-119 demonstrates dose-dependent inhibition of ear thickness in an IL-23-induced psoriasis mice model (0.3 mg\/kg, 1.0 mg\/kg and 3.0 mg\/kg). It also shows strong efficacy in reducing psoriasis clinical score in an imiquimod-induced mice psoriasis model (3 mg\/kg, 10 mg\/kg and 30 mg\/kg). In a DNFB-induced Atopic Dermatitis model, FZ007-119 (1 mg\/kg, 3 mg\/kg and 10 mg\/kg) significantly reduced lesion scores. FZ007-119 has favorable DMPK profiles, with low risk of drug-drug interactions, no significant inhibition of cytochrome P450 isozymes, and limited inhibition of BCRP or p-gp (IC50 &gt;10\u03bcM). It is not a substrate for various transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K). In addition, FZ007-119 exhibits remarkable PK properties and has demonstrated good oral bioavailability in rodents and dogs.<\/p>\n\n\n\n<p><strong>Conclusion:<\/strong>\u00a0Using our AI-driven drug design tools, we rapidly identified a highly potent and selective TYK2 inhibitor, FZ007-119. Preclinical data support the potential of FZ007-119 as a promising candidate for the treatment of IMIDs such as psoriasis and atopic dermatitis, offering an attractive therapeutic approach with improved efficacy and safety compared to non-selective JAK inhibitors.<\/p>\n\n\n\n<p><strong>Disclosures:<\/strong>&nbsp;<strong>W. Zhong<\/strong>: None;&nbsp;<strong>J. Lu<\/strong>: None;&nbsp;<strong>D. Chen<\/strong>: None;&nbsp;<strong>S. Zhang<\/strong>: None;&nbsp;<strong>D. Deng<\/strong>: None.<\/p>\n\n\n\n<p><strong>To cite this abstract in AMA style:<\/strong>Zhong W, Lu J, Chen D, Zhang S, Deng D. Preclinical Profiles of FZ007-119, a Highly Potent and Selective Tyk2 Inhibitor, for the Treatment of Immune Mediated Inflammatory Diseases [abstract].&nbsp;<em>Arthritis Rheumatol.<\/em>&nbsp;2023; 75 (suppl 9). https:\/\/acrabstracts.org\/abstract\/preclinical-profiles-of-fz007-119-a-highly-potent-and-selective-tyk2-inhibitor-for-the-treatment-of-immune-mediated-inflammatory-diseases\/. Accessed&nbsp;February 19, 2024.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Monday, November 13, 2023 Background\/Purpose:&nbsp;Tyrosine Kinase 2 (TYK2) is a signaling protein within the Janus kinase (JAK) family. It plays a crucial role in transmitting signals from pro-inflammatory cytokines like IL-23, IL-12, and Type I IFN, which contribute to Immune Mediated Inflammatory Diseases (IMIDs). Here we report a novel oral TYK2 inhibitor called FZ007-119, unlike [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":56,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[],"class_list":["post-77","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-pr"],"blocksy_meta":[],"featured_image_urls":{"full":["https:\/\/www.fulmz.com\/news\/wp-content\/uploads\/fermion-ai-biotech-5.jpg",900,476,false],"thumbnail":["https:\/\/www.fulmz.com\/news\/wp-content\/uploads\/fermion-ai-biotech-5-150x150.jpg",150,150,true],"medium":["https:\/\/www.fulmz.com\/news\/wp-content\/uploads\/fermion-ai-biotech-5-300x159.jpg",300,159,true],"medium_large":["https:\/\/www.fulmz.com\/news\/wp-content\/uploads\/fermion-ai-biotech-5-768x406.jpg",768,406,true],"large":["https:\/\/www.fulmz.com\/news\/wp-content\/uploads\/fermion-ai-biotech-5.jpg",900,476,false],"1536x1536":["https:\/\/www.fulmz.com\/news\/wp-content\/uploads\/fermion-ai-biotech-5.jpg",900,476,false],"2048x2048":["https:\/\/www.fulmz.com\/news\/wp-content\/uploads\/fermion-ai-biotech-5.jpg",900,476,false]},"post_excerpt_stackable":"<p>Monday, November 13, 2023 Background\/Purpose:&nbsp;Tyrosine Kinase 2 (TYK2) is a signaling protein within the Janus kinase (JAK) family. It plays a crucial role in transmitting signals from pro-inflammatory cytokines like IL-23, IL-12, and Type I IFN, which contribute to Immune Mediated Inflammatory Diseases (IMIDs). Here we report a novel oral TYK2 inhibitor called FZ007-119, unlike traditional kinase inhibitors that target the catalytic domain, which acts through an allosteric mechanism by binding to the pseudokinase Janus homology 2 regulatory domain (JH2) of the TYK2 enzyme. This specific mode of action allows selective inhibition of TYK2 without affecting other kinases. Current preclinical&hellip;<\/p>\n","category_list":"<a href=\"https:\/\/www.fulmz.com\/news\/category\/pr\/\" rel=\"category tag\">Press Release<\/a>","author_info":{"name":"Anita","url":"https:\/\/www.fulmz.com\/news\/author\/www-fulmz-com\/"},"comments_num":"0 comments","yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v21.9.1 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Preclinical Profiles of FZ007-119, a Highly Potent and Selective Tyk2 Inhibitor, for the Treatment of Immune Mediated Inflammatory Diseases - Fermion<\/title>\n<meta name=\"description\" content=\"Preclinical Profiles of FZ007-119, a Highly Potent and Selective Tyk2 Inhibitor, for the Treatment of Immune Mediated Inflammatory Diseases\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.fulmz.com\/news\/preclinical-profiles-of-fz007-119-a-highly-potent-and-selective-tyk2-inhibitor-for-the-treatment-of-immune-mediated-inflammatory-diseases\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Preclinical Profiles of FZ007-119, a Highly Potent and Selective Tyk2 Inhibitor, for the Treatment of Immune Mediated Inflammatory Diseases - 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