Abstract：
TYK2, a member of the JAK family of proximal membrane-bound tyrosine kinases, has emerged as an attractive target for the treatment of autoimmune diseases. Herein, we report the discovery of first-in-class potent and subtype-selective TYK2 degraders. By conjugating a TYK2 ligand from a known allosteric TYK2 inhibitor with a VHL ligand as the E3 ligase ligand via alkyl linkers of various lengths, we rapidly identified TYK2 degrader 5 with moderate TYK2 degradation activity. Degrader 5 induced TYK2 degradation without affecting the protein level of subtype kinases (JAK1, JAK2, and JAK3) in Jurkat cellular assays. Furthermore, modifying the TYK2 ligand moiety of degrader 5 yielded the more potent TYK2 degrader 37 with retained selectivity for JAKs. Our subtype-selective TYK2 degraders represent valuable chemical probes for investigating the biology of TYK2 degradation.
摘要：
TYK2，近端膜结合酪氨酸激酶JAK家族的成员，已成为治疗自身免疫性疾病的有吸引力的靶标。在这里，我们报告发现了一流的有效和亚型选择性TYK2降解剂。通过各种长度的烷基接头将来自已知变构TYK2抑制剂的TYK2配体与作为E3连接酶配体的VHL配体缀合，我们快速鉴定出具有中等TYK2降解活性的TYK2降解剂5。降解剂5在Jurkat细胞测定中诱导TYK2降解而不影响亚型激酶(JAK1、JAK2和JAK3)的蛋白质水平。此外，修饰降解剂5的TYK2配体部分产生更有效的TYK2降解剂37,并保留对JAK的选择性。我们的亚型选择性TYK2降解剂代表了研究TYK2降解生物学的有价值的化学探针。
