2. Academic Validation
  3. Arylidene-Thiazoldione Scaffold Acts as the E3 Ligand of DCAF11 for PROTAC Design

Arylidene-Thiazoldione Scaffold Acts as the E3 Ligand of DCAF11 for PROTAC Design

  • J Med Chem. 2026 Feb 12;69(3):2349-2369. doi: 10.1021/acs.jmedchem.5c02188.
Jinyi Liang 1,  Yuyang Liu 1,  Man Zhao 1 2,  Lu Chen 1,  Jiajie Qin 1,  Wenjing Ma 1,  Ying Wang 3,  Haiqiang Wu 1,  Ruilin Tian 4,  Tianzi Wei 4,  Lingyin Lao 1,  Jingfei Wang 1,  Hengyu Qu 1,  Hongbo Wang 1,  Rongfang Gao 1,  Sihan Guo 1,  Ming Zhang 1,  Liang Hong 2,  Rui Wang 1 5,  Guofeng Li 1
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
  • 2 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 3 Department of Cardiology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, 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 Institute of Materia Medica and Research Unit of Peptide Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 41628916 DOI: 10.1021/acs.jmedchem.5c02188
Abstract

E3 Ligases are crucial to PROTAC technology, and identifying novel E3 Ligase ligands could accelerate the advancement of PROTACs. DCAF11 has shown considerable potential for PROTAC applications. However, the ligands targeting DCAF11 remain limited, highlighting the need for the development of novel ligands for this E3 Ligase. In this study, leveraging previous research on DCAF11 ligands, we designed a class of arylidene-thiazoldione scaffolds and applied it to develop PROTACs, resulting in the identification of a potent BRD4 Degrader, LGF308. Degradation activity and mechanistic studies demonstrated that the compound LGF308 efficiently induces BRD4 degradation through the proteasomal pathway and via recruitment of DCAF11. This scaffold represents a reliable ligand, capable of facilitating the degradation of various proteins, including CDK4/6, Btk, and FKBP12. Therefore, this study introduces the arylidene-thiazoldione scaffold as a novel DCAF11 ligand and validates its application in PROTAC design, providing strong support for the development of DCAF11-based PROTACs.

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