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.

TYK2 是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。在此，我们报告了一流的强效亚型选择性 TYK2 降解剂的发现。通过将已知变构TYK2抑制剂的TYK2配体与作为E3连接酶配体的VHL配体通过不同长度的烷基接头缀合，我们快速鉴定了具有中等TYK2降解活性的TYK2降解剂5 。在 Jurkat 细胞检测中，Degrader 5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 配体部分产生了更有效的 TYK2 降解剂37 ，并保留了对 JAK 的选择性。我们的亚型选择性 TYK2 降解剂是研究 TYK2 降解生物学的有价值的化学探针。