Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways

作者：Yu Zhou, Xin Li, Ru Shen, Xiangzhu Wang, Fan Zhang, Suxing Liu, Di Li, Jian Liu, Puhui Li, Yinfa Yan, Ping Dong, Zhigao Zhang, He‐Ping Wu, Linghang Zhuang, Rasheduzzaman Chowdhury, Matthew J. Miller, Mena Issa, Yuchang Mao, Hongli Chen, Jun Feng, Jing Li, Chang Bai, Feng He, Weikang Tao · 发表于：Frontiers in Immunology · 年份：2022 · DOI：10.3389/fimmu.2022.884399 · 被引用次数：29 · 研究领域：Cytokine Signaling Pathways and Interactions、Protein Kinase Regulation and GTPase Signaling、Melanoma and MAPK Pathways

A member of the Janus kinase (JAK) family, Tyrosine Kinase 2 (TYK2), is crucial in mediating various cytokine-signaling pathways such as interleukin-23 (IL23), interleukin-12 (IL12) and type I Interferons (IFN) which contribute to autoimmune disorders (e.g., psoriasis, lupus, and inflammatory bowel disease). Thus, TYK2 represents an attractive target to develop small-molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. Selective inhibition of TYK2 over other JAK isoforms is critical to achieve a favorable therapeutic index in the development of TYK2 inhibitors. However, designing small molecule inhibitors to target the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the substantial structural homology of the JAK family catalytic domains. Here, we employed an approach to target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. We developed a series of small-molecule TYK2 pseudokinase ligands, which suppress the TYK2 catalytic activity through allosteric regulation. The TYK2 pseudokinase-binding small molecules in this study simultaneously achieve high affinity-binding for the TYK2 JH2 domain while also affording significantly reduced affinity for the TYK2 JAK homology 1 (JH1) kinase domain. These TYK2 JH2 selective molecules, although possessing little effect on suppressing the catalytic activity of the isolated TYK2 JH1 catalytic domain in the kinase assays, can still significantly bl...