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

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

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118374. doi: 10.1016/j.ejmech.2025.118374.
Gang Li 1,  Yanghui Ou 1,  Yuanhui Liu 2,  Jun Wang 1,  Zhuoran He 3,  Xinshan Deng 4,  Wei Pan 1,  Mian Peng 5,  Chuxun Zhou 1,  Jiayu Li 1,  Yali Zhang 1,  Shuting Zou 4,  Hongliang Yao 6
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, 510260, Guangdong, China.
  • 2 Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, 510260, Guangdong, China; Pharmacy Department, Yuexi Hospital of the Sixth Affiliated Hospital, Sun Yat-sen University (Xinyi People's Hospital), Xinyi, 525300, China.
  • 3 Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, 510260, Guangdong, China; Department of Critical Care Medicine, Luohu Clinical Institute of Shantou University Medical College, Guangdong, 518001, China.
  • 4 Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, 410219, Hunan, China.
  • 5 Department of Critical Care Medicine, Luohu Clinical Institute of Shantou University Medical College, Guangdong, 518001, China.
  • 6 Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, 510260, Guangdong, China. Electronic address: [email protected].
PMID: 41270647 DOI: 10.1016/j.ejmech.2025.118374
Abstract

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.

Keywords

Degrader; Inflammatory bowel diseases; JAK; PROTAC.

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