2. Academic Validation
  3. Discovery of Ibrutinib-based BTK PROTACs with in vivo anti-inflammatory efficacy by inhibiting NF-κB activation

Discovery of Ibrutinib-based BTK PROTACs with in vivo anti-inflammatory efficacy by inhibiting NF-κB activation

  • Eur J Med Chem. 2023 Nov 5;259:115664. doi: 10.1016/j.ejmech.2023.115664.
Junli Huang 1,  Zeli Ma 2,  Zichao Yang 1,  Zengzhu He 3,  Jingna Bao 2,  Xiaopeng Peng 4,  Yao Liu 5,  Ting Chen 6,  Shumin Cai 7,  Jianjun Chen 8,  Zhenhua Zeng 9
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
  • 4 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Province Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China.
  • 5 Instrumental Analysis Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
  • 6 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: 252199453@qq.com.
  • 7 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. Electronic address: 13751845166@163.com.
  • 8 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: jchen21@smu.edu.cn.
  • 9 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. Electronic address: zhenhuazeng.2008@163.com.
PMID: 37487306 DOI: 10.1016/j.ejmech.2023.115664
Abstract

As a critical upstream regulator of nuclear factor-κB (NF-κB) activation, Bruton's tyrosine kinase (Btk) has been identified to be an effective therapeutic target for the treatment of acute or chronic inflammatory diseases. Herein, we describe the design, synthesis and structure-activity-relationship analysis of a novel series of Ibrutinib-based BTK PROTACs by recruiting Cereblon (CRBN) Ligase. Among them, compound 15 was identified as the most potent degrader with a DC50 of 3.18 nM, significantly better than the positive control MT802 (DC50 of 63.31 nM). Compound 15 could also degrade Btk protein in Lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and suppress the mRNA expression and secretion of proinflammatory cytokines such as IL-1β and IL-6 by inhibiting NF-κB activation. Furthermore, compound 15 reduced inflammatory responses in a mouse zymosan-induced peritonitis (ZIP) model. Our findings demonstrated for the first time that targeting Btk degradation by PROTACs might be an alternative option for the treatment of inflammatory disorders, and compound 15 represents one of the most efficient BTK PROTACs (DC50 = 3.18 nM; Dmax = 99.90%; near 100% degradation at 8 h) reported so far and could serve as a lead compound for further investigation as an anti-inflammatory agent.

Keywords

BTK; Inflammation; NF-κB; PROTAC degrader.

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