2. Academic Validation
  3. Discovery of novel PDE4 degraders with in vivo anti-inflammatory efficacy

Discovery of novel PDE4 degraders with in vivo anti-inflammatory efficacy

  • Bioorg Chem. 2025 Jun 6:163:108675. doi: 10.1016/j.bioorg.2025.108675.
Yuanhui Liu 1,  Hongliang Yao 2,  Yanghui Ou 2,  Lishan Hu 2,  Wei Pan 2,  Mengjie Li 2,  Yali Zhang 2,  Jun Wang 2,  Jiaxin Chen 3,  Xudong Qian 2,  Jiayu Li 2,  Peiming Huang 2,  Gong Chen 3,  Gang Li 4,  Lianbao Ye 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; 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, Guangdong 510260, 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, Guangdong 510260, China.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
  • 4 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, Guangdong 510260, China. Electronic address: ligang@giz.gd.cn.
  • 5 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address: yelb7909@163.com.
PMID: 40513451 DOI: 10.1016/j.bioorg.2025.108675
Abstract

Phosphodiesterase 4 (PDE4) has been identified to be an effective target for treatment of autoimmune and inflammatory diseases like chronic obstructive pulmonary disease (COPD), psoriasis and asthma. To overcome the selectivity problem, PDE4 degraders based on the proteolysis-targeting chimera (PROTAC) technology might be an alternative choose. Herein, a novel series of PDE4 PROTACs by recruiting Cereblon (CRBN) Ligase were designed and synthesized. Among them, compound 9 m could suppress the secretion of pro-inflammatory cytokines such as TNF-α and IL-6 in LPS-stimulated Raw264.7 cells (IC50 = 43.25 μM, 53.79 μM). More importantly, 9 m could degrade PDE4B selectively (DC50 = 41.98 μM). Furthermore, we discovered that 9 m significantly reduced the infiltration of inflammatory cells into lung tissue to protect lung tissues and alleviate acute lung injury (ALI). Besides, 9 m exhibits moderate oral bioavailability (F%) of 21 %. Taken together, 9 m represents a novel PDE4 degrader deserving further development as a new lead compound for inflammatory diseases.

Keywords

Acute lung injury; Degrader; PDE4; PROTAC.

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