Development of potent JAK1/2 PROTAC degraders for the treatment of inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) is a chronic, progressive disorder, which imposes a substantial global health burden. The current scarcity of safer and more efficacious clinical treatment for IBD underscores the urgent need to develop novel drugs. Proteolysis-targeting chimera (PROTAC) technology has surfaced as a ground-breaking therapeutic approach to facilitate drug discovery. Herein, a novel series of PROTAC degraders based on momelotinib were designed and synthesised. Among the PROTAC degraders, compound A8 degraded JAK1 and JAK2 with DC50 values of 1.4 and 0.92 μM, respectively. Additionally, A8 suppressed the secretion of pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in lipopolysaccharide-stimulated Raw 264.7 cells (IC50 = 17.17 and 12.89 μM, respectively). Mechanistic investigations revealed that A8 triggers JAK1/2 degradation through a pathway reliant on CRBN and the proteasome system. Furthermore, in vivo studies demonstrated that A8 significantly reduced inflammatory responses and colon injury by suppressing the JAK/STAT3 signalling pathway. Overall, A8 represents a novel JAK1/2 degrader as a lead compound for IBD for the first time, which deserves further development.