PROteolysis TArgeting Chimera (PROTAC) is an emerging technology in chemical biology and drug discovery. This technique facilitates the complete removal of the target proteins that are “undruggable” or challenging to target through chemical molecules via the Ubiquitin–Proteasome System (UPS). PROTACs have been widely explored and outperformed not only in cancer but also in other diseases. During the past few decades, several academic institutes and pharma companies have poured more efforts into PROTAC-related technologies, setting the stage for several major degrader trial readouts in clinical phases. Despite their promising results, the formation of robust ternary orientation, off-target activity, poor permeability, and binding affinity are some of the limitations that hinder their development. Recent advancements in computational technologies have facilitated progress in the development of PROTACs. Researchers have been able to utilize these technologies to explore a wider range of E3 ligases and optimize linkers, thereby gaining a better understanding of the effectiveness and safety of PROTACs in clinical settings. In this review, we briefly explore the computational strategies reported to date for the formation of PROTAC components and discuss the key challenges and opportunities for further research in this area.

Eun-Ji Ko, Kyoung Seob Song, Mee Sun Ock, Yung Hyun Choi, Suhkmann Kim, Heui-Soo Kim & Hee-Jae Cha. BMB Reports 2021;54:368-73. https://doi.org/10.5483/BMBRep.2021.54.7.246

Recently, it was found that IL-13 is involved in allergic inflammation and mucus hypersecretion in in vivo animal models. However, the role of IL-13 in in vitro cellular models has yet to be determined. This study aimed to investigate the direct effect of IL-13 on mucin gene expression and mucin secretion in cultured normal human nasal epithelial cells. After treatment with IL-13, total mucin and MUC5AC mucin levels were measured using an immunoblotting assay. MUC2, MUC5AC and MUC8 mRNA expression were determined using reverse transcription-polymerase chain reaction. Also, immunostaining was performed using a MUC5AC antibody on histologic and cytospin slides. After treatment with S 5 ng/ml IL-13, the level of total mucin and MUC5AC mucin secretion decreased substantially. The expression of MUC2 and MUC8 mRNA increased with higher concentrations of IL-13, but the expression of MUC5AC mRNA decreased. On the 7th day after IL-13 treatment, a significant decrease in the number of MUC5AC-positive cells was confirmed by immunostaining. These findings indicate that IL-13 suppresses MUC5AC mucin gene expression and mucin secretion in cultured normal human nasal epithelial cells in vitro .

Iron homeostasis is considered a key factor in human metabolism, and abrogation in the system could create adverse effects, including cancer. Moreover, 6-gingerol is a widely used bioactive phenolic compound with anticancer activity, and studies on its exact mechanisms on non-small cell lung cancer (NSCLC) cells are still undergoing. This study aimed to find the mechanism of cell death induction by 6-gingerol in NSCLC cells. Western blotting, real-time polymerase chain reaction, and flow cytometry were used for molecular signaling studies, and invasion and tumorsphere formation assay were also used with comet assay for cellular processes. Our results show that 6-gingerol inhibited cancer cell proliferation and induced DNA damage response, cell cycle arrest, and apoptosis in NSCLC cells, and cell death induction was found to be the mitochondrial-dependent intrinsic apoptosis pathway. The role of iron homeostasis in the cell death induction of 6-gingerol was also investigated, and iron metabolism played a vital role in the anticancer ability of 6-gingerol by downregulating EGFR/JAK2/STAT5b signaling or upregulating p53 and downregulating PD-L1 expression. Also, 6-gingerol induced miR-34a and miR-200c expression, which may indicate regulation of PD-L1 expression by 6-gingerol. These results suggest that 6-gingerol could be a candidate drug against NSCLC cells and that 6-gingerol could play a vital role in cancer immunotherapy.

Sang-Su Kim, Cheol Hong Kim, Ji Wook Kim, Hsi Chiang Kung, Tae Woo Park, Yu Som Shin, Ju Deok Kim, Siejeong Ryu, Wang-Joon Kim, Yung Hyun Choi & Kyoung Seob Song. BMB Reports 2017;50:516-21. https://doi.org/10.5483/BMBRep.2017.50.10.100

Urban particulate matter (UPM) is recognized as a grave public health problem worldwide. Although a few studies have linked UPM to ocular surface diseases, few studies have reported on retinal dysfunction. Thus, the aim of the present study was to evaluate the influence of UPM on the retina and identify the main mechanism of UPM toxicity. In this study, we found that UPM significantly induced cytotoxicity with morphological changes in ARPE-19 human retinal pigment epithelial (RPE) cells and increased necrosis and autophagy but not apoptosis. Furthermore, UPM significantly increased G2/M arrest and simultaneously induced alterations in cell cycle regulators. In addition, DNA damage and mitochondrial dysfunction were remarkably enhanced by UPM. However, the pretreatment with the potent reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) effectively suppressed UPM-mediated cytotoxicity, necrosis, autophagy, and cell cycle arrest. Moreover, NAC markedly restored UPM-induced DNA damage and mitochondrial dysfunction. Meanwhile, UPM increased the expression of mitophagy-regulated proteins, but NAC had no effect on mitophagy. Taken together, although further studies are needed to identify the role of mitophagy in UPM-induced RPE injury, the present study provides the first evidence that ROS-mediated cellular damage through necrosis and autophagy is one of the mechanisms of UPM-induced retinal disorders.