2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel BTK-targeting proteolysis targeting chimeras (PROTACs) with enhanced pharmacokinetic properties

Design, synthesis, and biological evaluation of novel BTK-targeting proteolysis targeting chimeras (PROTACs) with enhanced pharmacokinetic properties

  • Eur J Med Chem. 2025 May 5:289:117420. doi: 10.1016/j.ejmech.2025.117420.
Ying Lin 1,  Jing Liu 2,  Xinjian Tian 1,  Jin Wang 1,  Huahua Su 1,  Jianpin Xiang 3,  Tao Cao 3,  Yonghui Wang 1,  Qiong Xie 4,  Xufen Yu 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, Shanghai, 201203, China.
  • 2 Department of Pharmacy, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Shanghai, Shanghai, 200240, China.
  • 3 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, Shanghai, 201203, China. Electronic address: qxie@fudan.edu.cn.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, Shanghai, 201203, China; Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, Shanghai, 201203, China; MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai, Shanghai, 201203, China. Electronic address: yuxufen@fudan.edu.cn.
PMID: 40037061 DOI: 10.1016/j.ejmech.2025.117420
Abstract

Bruton's tyrosine kinase (Btk) has been an attractive target in the B-cell malignancies. Significant progress has been achieved in developing effective BTK-targeting small-molecule inhibitors and proteolysis targeting chimeras (PROTACs). Based on noncovalent inhibitor ARQ-531, we previously developed two potent BTK PROTACs 6e and SC-3e, which exhibited poor pharmacokinetic property. Herein, we present our extensive structure-activity relationship (SAR) studies focused on Btk binder, linker and Cereblon (CRBN) ligand of SC-3e, resulting in two novel BTK PROTACs FDU28 (compound 25) and FDU73 (compound 27). Compounds 25 and 27 selectively induced rapid and robust degradation of wild type (WT) and C481S mutant Btk in a concentration-, time- and ubiquitin-proteasome system (UPS)-dependent manner without affecting CRBN neo-substrates. Furthermore, compound 27 displayed excellent cell antiproliferative activities, metabolic stability in mouse liver microsomes and improved bioavailability in mice. Overall, 27 is a highly effective and selective Btk degrader that is suitable for in vivo efficacy investigations.

Keywords

B-Cell malignancies; BTK; PROTAC; Pharmacokinetic property; SAR study.

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