2. Academic Validation
  3. Semi-rigid linkers improve the pharmacokinetic properties and therapeutic efficacy of BET PROTACs for cancer therapy

Semi-rigid linkers improve the pharmacokinetic properties and therapeutic efficacy of BET PROTACs for cancer therapy

  • Eur J Med Chem. 2026 Apr 5:307:118644. doi: 10.1016/j.ejmech.2026.118644.
Su Yu 1,  Shichuan Hu 2,  Weilin Wang 3,  Chuntao Pan 4,  Hongjia Zhang 5,  Cong Zhou 6,  Yang Liu 7,  Rui Li 8
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: 2903787408@qq.com.
  • 2 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: 958656223@qq.com.
  • 3 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: 2023324065111@stu.scu.edu.cn.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: 203720937@qq.com.
  • 5 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: 1695174695@qq.com.
  • 6 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zhoucongnoi@163.com.
  • 7 Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, 610041, China; General Surgery Center, The Second People's Hospital of Yibin City, Sichuan Province, 644000, China. Electronic address: liuyang@wchscu.cn.
  • 8 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: lirui@scu.edu.cn.
PMID: 41687266 DOI: 10.1016/j.ejmech.2026.118644
Abstract

PROTACs offer a novel therapeutic strategy for addressing diseases driven by aberrant expression of pathogenic proteins. In this study, we identified a series of PROTAC molecules capable of degrading BRD2, BRD3, and BRD4. Structure-activity relationship analysis led to the discovery of CR10, a highly potent degrader that exhibited remarkable activity in MV4-11 cells. Mechanistic studies demonstrated that CR10 induced sustained degradation of target proteins via the ubiquitin-proteasome system. In mice models, intraperitoneal administration at 20 mg/kg achieved an exceptional bioavailability of 108.27%. Furthermore, CR10 significantly inhibited the growth of MV4-11 and A549 xenograft tumors at a dose as low as 2 mg/kg, without apparent toxicity. This semi-rigid linker-containing degrader represented a promising new mechanism-based candidate for the treatment of hematologic malignancies and lung Cancer, warranting further investigation.

Keywords

BET; Degrader; Inhibitors; Linker; PROTAC.

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