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.
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Article Synopsis
- Protein disulphide isomerases (PDIs) are crucial in cancer progression, but their specific roles in tumor formation are still unclear.
- In a study of 22 cancer cell lines, PDIA1 and PDIA3 were found to be the most abundant isoforms, while PDIA17 showed varying expression levels across different cell lines.
- Inhibition of PDIA1 and PDIA3 led to significant anti-proliferative effects in breast cancer cells, with the most notable effects seen in hormone-sensitive MCF-7 cells, suggesting potential strategies for targeted cancer therapies.
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