Liu Shiwei,Yuan Fukang,Dong Hui,Zhang Jiaqi,Mao Xinyu,Liu Yangsui,Li Huansong
Background Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, and the lack of effective biomarkers for early detection leads to poor therapeutic outcomes. Prostaglandin E Synthase 3 (PTGES3) is a putative prognostic marker in many solid tumors; however, its expression and biological functions in HCC have not been determined. The proteolysis-targeting chimera (PROTAC) is an established technology for targeted protein degradation. Compared to the small-molecule PROTAC, the peptide PROTAC (p-PROTAC) utilizes peptides bound to target proteins to mediate the ubiquitination and degradation of undruggable proteins. This study aimed to use the PROTAC technology to develop a PTGES3 degrader liposome complex containing a PTGES3-binding peptide and the E3 ubiquitin ligase ligand pomalidomide for regulating cell function and provide a novel pathway for treating HCC. Results In this study, we demonstrated that PTGES3 is highly expressed in HCC at the transcriptional and protein levels; furthermore, PTGES3 was identified as a novel drug target that could potentially treat HCC. Hence, we developed PTGES3-PROTACs by adjusting the ligand ratio to optimize the efficacy of degradation agents. The results revealed that PTGES3-PROTAC effectively degraded PTGES3 protein and strongly weakened the HCC malignant phenotype in vitro and in vivo. Conclusions Our findings revealed that the highly selective PTGES3 proteolysis is a potential therapeutic strategy for HCC, and PTGES3 degraders PTGES3-PROTACs can be developed as safe and effective drugs for HCC treatment. Graphical abstract
In order to explore novel immunomodulatory agents as anti-tumor drugs, we designed and synthesized a series of new pomalidomide derivatives containing urea moieties. Interestingly, in vitro biological experiments performed in several cancer cell lines showed that some of them displayed potent anti-tumor ability. These novel compounds5a–5eand6a–6edemonstrated the best cell growth inhibitive activity in human breast cancer cell lines MCF-7, but weaker inhibitive activity in human hepatocellular carcinoma cell lines Huh7. Moreover, compound5dhad the most powerful effects in this study, with an IC50value of 20.2 μM in MCF-7. Further study indicated that compound5dcould inhibit cell growth and induce cell death in a concentration-dependent manner. Besides, compound5dincreased cellular ROS levels and induced DNA damage, thereby potentially leading to cell apoptosis. These observations suggest that the novel pomalidomide derivatives containing urea moieties may be worth further investigation to generate potential anti-tumor drugs.Keywords:pomalidomide derivatives;urea moieties;immunomodulatory;anti-tumor effects
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