Abstract：
Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.
摘要：
JAK-STAT途径的异常激活在包括癌症的各种人类疾病中是明显的。蛋白水解靶向嵌合体(PROTACs)为开发新的JAK靶向药物提供了有吸引力的策略。在这里，利用JAK1/JAK2双重抑制剂-莫美罗替尼作为弹头，设计并合成了一系列CRBN导向的JAK靶向PROTACs。最有希望的化合物10c表现出良好的酶促效力和细胞抗增殖作用。Western印迹分析揭示化合物10c以蛋白酶体依赖性方式有效且选择性地降解JAK1(DC50=214nM)。此外，PROTAC10c显著抑制了JAK1及其关键下游信令。一起,化合物10c可以作为抗肿瘤药物发现的新型先导化合物。
