2. Academic Validation
  3. Azoacetylene Electrophiles for Proteome-wide Ligand and Target Discovery: Supporting Targeted Protein Degradation

Azoacetylene Electrophiles for Proteome-wide Ligand and Target Discovery: Supporting Targeted Protein Degradation

  • J Med Chem. 2025 Jul 10;68(13):13516-13531. doi: 10.1021/acs.jmedchem.5c00229.
Jiayi Du 1 2 3,  Shengrong Li 4,  Fang Xu 1 2 3,  Zehong Lin 1 2 3,  Tongyi Hong 1 2 3,  Yifang Li 1 2 3,  Zeyi Deng 5,  Yi Tan 1 2 3,  Zhengqiu Li 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 3 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4 Guangdong Second Provincial General Hospital, Postdoctoral Station of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China.
  • 5 Department of Otorhinolaryngology, Head and Neck Surgery, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou 510317, China.
PMID: 40566838 DOI: 10.1021/acs.jmedchem.5c00229
Abstract

Covalent probes integrated with chemical proteomics have been an efficient method for disclosing new druggable targets and E3 ubiquitin ligases supporting targeted protein degradation. However, a large fraction of the proteome including E3 Ligases remains inaccessible with existing electrophiles. In this work, we developed a new reactive warhead, terminal azoacetylene, which can be generated by in situ desilylation for proteome profiling under cellular conditions. A series of uncharacterized targets and E3 ubiquitin ligases were covalently engaged. Fragment-based ligand discovery (FBLD) showed that the azoacetylene-containing fragments can covalently bind a series of essential protein hits at the active sites such as C130 of TUFM probably modulating the protein functions. Incorporation of this warhead into BRD4 targeting inhibitor JQ1 led to generation of novel small molecular degraders that degrade BRD4 without inducing the hook effect. This provides a new method for ligand and target discovery, as well as the development of new types of small molecular degraders.

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