A Versatile Bioorthogonal Theranostic Platform Enables Relay Activation of Tumor Cell Imaging and Targeted Protein Degradation

  • J Am Chem Soc. 2025 Nov 27. doi: 10.1021/jacs.5c11564.
Feilong Sun  1 ,  Tian Wang  2 ,  Pengfei Wang  3  4 ,  Jiaxin Shi  2 ,  Yanyan Shen  3 ,  Guilong Wang  5 ,  Biyu Yang  3 ,  Huiwen Li  1  4 ,  Qiumeng Zhang  1 ,  Yi Chen  3  4 ,  Xuan Zhang  1  2  4
Affiliations
  • 1. Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 41311144 DOI: 10.1021/jacs.5c11564
Abstract

Targeted protein degradation offers therapeutic promise but often suffers from on-target off-tissue toxicities. To overcome this challenge, we developed a versatile theranostic platform that integrates tumor cell imaging with precisely controlled protein degradation. Central to this platform is XZ2223, a glutathione (GSH)-cleavable bioorthogonal trigger that couples Cancer cell labeling with concomitant tetrazine release, thereby activating trans-cyclooctene (TCO)-caged CRBN-recruiting degrader prodrugs, Pro-CC-885 and Pro-dBET6, to induce on-demand degradation of GSPT1 and BET, respectively. Coadministration of XZ2223 with either prodrug afforded robust tumor imaging and efficient protein degradation in xenograft models, while the XZ2223/Pro-dBET6 combination further elicited in vivo antitumor efficacy with reduced systemic toxicity. This innovative platform shows potential as a dual-function approach for precision Cancer therapy.

Products