2. Academic Validation
  3. Design and evaluation of selective BET PROTACs with potent antitumor efficacy and safety against acute myeloid leukemia

Design and evaluation of selective BET PROTACs with potent antitumor efficacy and safety against acute myeloid leukemia

  • Eur J Med Chem. 2026 Apr 15:308:118667. doi: 10.1016/j.ejmech.2026.118667.
Qingyun Wei 1,  Jian Zhang 2,  Jiao Chen 1,  Xueting Cai 1,  Jinpei Zhou 2,  Bo Wang 3,  Huibin Zhang 4,  Peng Cao 5
Affiliations

Affiliations

  • 1 Jiangsu Provincial Integrated Innovation Center of Hospital Preparations, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, PR China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210028, PR China.
  • 2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 3 Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China. Electronic address: bwang@njucm.edu.cn.
  • 4 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: zhanghb80@163.com.
  • 5 Jiangsu Provincial Integrated Innovation Center of Hospital Preparations, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, PR China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210028, PR China; Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, PR China. Electronic address: cao_peng@njucm.edu.cn.
PMID: 41740583 DOI: 10.1016/j.ejmech.2026.118667
Abstract

Targeting bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for acute myeloid leukemia (AML). However, clinical development of conventional BET inhibitors has been limited by dose-related toxicities and compensatory resistance. Proteolysis-targeting chimeras (PROTACs) offer a catalytic and often more selective alternative by degrading target proteins via the ubiquitin-proteasome system. In this work, we designed and synthesized a series of novel BET PROTACs based on the clinical inhibitor ABBV-075. Through systematic optimization of linker length/composition and E3 Ligase ligands (CRBN or VHL), we identified two highly potent PROTACs, A10 (CRBN-based) and A12 (VHL-based). Both compounds effectively degraded BET proteins, inhibited cell proliferation, induced cell-cycle arrest, and promoted Apoptosis in MV4-11 AML cells. In MV4-11 xenograft models, A10 (6 mg/kg) and A12 (2 mg/kg) demonstrated significant tumor growth inhibition (76.2% and 60.5%, respectively). A comprehensive drug-likeness assessment revealed that while A12 exhibited higher systemic exposure in pharmacokinetic studies, A10 displayed a markedly superior safety profile with minimal hepatorenal toxicity. The favorable efficacy-safety balance of A10 underscores its strong potential as a preclinical candidate for AML therapy. This study highlights how rational PROTAC optimization can yield degraders with enhanced therapeutic windows, providing a promising path forward for targeted protein degradation in AML.

Keywords

BET degradation; E3 ligase; Evaluation; PROTAC.

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