2. Academic Validation
  3. Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair

Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair

  • J Med Chem. 2024 Nov 14;67(21):19428-19447. doi: 10.1021/acs.jmedchem.4c01767.
Man Zhao 1 2 3,  Wenjing Ma 1,  Jinyi Liang 1,  Yubao Xie 1,  Tianzi Wei 4,  Ming Zhang 1,  Jiajie Qin 1,  Lingyin Lao 1,  Ruilin Tian 4,  Haiqiang Wu 1,  Jin Cheng 5,  Min Li 3,  Yuyang Liu 1 2,  Liang Hong 3,  Guofeng Li 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
  • 2 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
  • 3 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 4 Key University Laboratory of Metabolism and Health of Guangdong, Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
  • 5 The Affiliated Wuxi Center for Disease Control and Prevention, Wuxi Center for Disease Control and Prevention, Nanjing Medical University, Wuxi 214023, China.
PMID: 39475482 DOI: 10.1021/acs.jmedchem.4c01767
Abstract

Proteolytic targeting chimera (PROTAC) represent an advanced strategy for targeting undruggable proteins, and the molecular warheads targeting E3 Ligases play a crucial role. Recently, we explored an alkenyl oxindole warhead targeting the E3 Ligase DCAF11 and sought to validate its potential. In this study, we synthesized a range of BRD4 PROTACs (8a-8o, 14a-14f, 22a-22m) with modified alkenyl oxindole warheads and developed a high-throughput screening system based on high-content imaging. We identified L134 (22a) as a potent BRD4 Degrader, achieving BRD4 degradation (Dmax > 98%, DC50 = 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by L134 was mediated through the ubiquitin-proteasome system in a DCAF11-dependent manner. Therefore, this study provides a rapid screening method for effective PROTACs and highlights the PROTAC L134 based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers.

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