Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases
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 select...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223014099 |
| _version_ | 1797660516703797248 |
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| author | Zhiqin Fang Hongyin Sun Yutong Wang Zhenliang Sun Mingzhu Yin |
| author_facet | Zhiqin Fang Hongyin Sun Yutong Wang Zhenliang Sun Mingzhu Yin |
| author_sort | Zhiqin Fang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T18:32:03Z |
| format | Article |
| id | doaj.art-821ccdd4a6f5469ea8bc7055a11317b2 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T18:32:03Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-821ccdd4a6f5469ea8bc7055a11317b22023-10-13T11:03:19ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-11-01167115611Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseasesZhiqin Fang0Hongyin Sun1Yutong Wang2Zhenliang Sun3Mingzhu Yin4Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Southern Medical University Affiliated Fengxian Hospital, Shanghai, ChinaClinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan, ChinaSouthern Medical University Affiliated Fengxian Hospital, Shanghai, China; Corresponding author.Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, China; Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC), Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, China; Translational Medicine Research Center (TMRC), School of Medicine Chongqing University, Shapingba, Chongqing, China; Corresponding author at: Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, China.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.http://www.sciencedirect.com/science/article/pii/S0753332223014099JAKTYK2 inhibitorSLEPsoriasisIBDAutoimmune diseases |
| spellingShingle | Zhiqin Fang Hongyin Sun Yutong Wang Zhenliang Sun Mingzhu Yin Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases Biomedicine & Pharmacotherapy JAK TYK2 inhibitor SLE Psoriasis IBD Autoimmune diseases |
| title | Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases |
| title_full | Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases |
| title_fullStr | Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases |
| title_full_unstemmed | Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases |
| title_short | Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases |
| title_sort | discovery of wd 890 a novel allosteric tyk2 inhibitor for the treatment of multiple autoimmune diseases |
| topic | JAK TYK2 inhibitor SLE Psoriasis IBD Autoimmune diseases |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223014099 |
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