2. Academic Validation
  3. Unveiling a new strategy for PDIA1 inhibition: Integration of activity-based probes profiling and targeted degradation

Unveiling a new strategy for PDIA1 inhibition: Integration of activity-based probes profiling and targeted degradation

  • Bioorg Chem. 2024 Sep:150:107585. doi: 10.1016/j.bioorg.2024.107585.
Bei Zhang 1,  Dawei Hong 1,  Hujuan Qian 1,  Keqing Ma 1,  Liquan Zhu 2,  Linye Jiang 1,  Jingyan Ge 3
Affiliations

Affiliations

  • 1 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China.
  • 2 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China; General Surgery, Department of Breast Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
  • 3 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address: gejy@zjut.edu.cn.
PMID: 38917491 DOI: 10.1016/j.bioorg.2024.107585
Abstract

The overexpression of PDIA1 in Cancer has spurred the quest for effective inhibitors. However, existing inhibitors often bind to only one active site, limiting their efficacy. In our study, we developed a PROTAC-mimetic probe dPA by combining PACMA31 (PA) analogs with cereblon-directed pomalidomide. Through protein profiling and analysis, we confirmed dPA's specific interaction with PDIA1's active site cysteines. We further synthesized PROTAC variants with a thiophene ring and various linkers to enhance degradation efficiency. Notably, H4, featuring a PEG linker, induced significant PDIA1 degradation and inhibited Cancer cell proliferation similarly to PA. The biosafety profile of H4 is comparable to that of PA, highlighting its potential for further development in Cancer therapy. Our findings highlight a novel strategy for PDIA1 inhibition via targeted degradation, offering promising prospects in Cancer therapeutics. This approach may overcome limitations of conventional inhibitors, presenting new avenues for advancing anti-cancer interventions.

Keywords

Activity based probe profiling; PDIA1; PROTACs; Proteomics; Targeted protein degradation.

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