Photo-regulated PROTACs: A novel tool for temporal control of targeted protein degradation.

PROTACs (Proteolysis targeting chimeras) are chimeric molecules designed to induce targeted protein degradation via the ubiquitin-proteasome system. These molecules catalytically degrade target proteins and sustainably inhibit their function. Therefore, PROTAC's unique mechanism of action is not only beneficial in medicine but also serves as a valuable tool for molecular biological analysis in fields like chemical biology, biochemistry, and drug discovery. This study presents a novel turn-off (ON-OFF) type PROTAC development strategy utilizing a photocleavable linker. The inclusion of this linker enables temporal control of the degradation activity targeting BRD4 protein upon UV light exposure. PROTAC-2 demonstrated the most potent degradation activity against BRD4 among the other synthesized PROTACs with varying linker lengths. The UV light-induced cleavage of PROTAC-2 was confirmed, leading to a reduction in its BRD4 degradation activity. Notably, this study introduces a novel linker capable of nullifying degradation activity of PROTACs which is activated by light irradiation. These findings offer a promising strategy for the development of turn-off type PROTACs, providing enhanced temporal control over protein degradation. The approach holds significant potential for applications in molecular function studies and drug discovery.

Development of versatile solid-phase methods for syntheses of PROTACs with diverse E3 ligands.

Developing highly active proteolysis-targeting chimeras (PROTACs) requires investigating a variety of ubiquitin ligase (E3 ligase) ligands and linker structures as well as their lengths. In this study, we developed a solid-phase synthesis method that affords PROTAC design diversity. We expanded the E3 ligand range to include Von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) ligands because only the cereblon (CRBN) ligand thalidomide and its derivatives have been investigated for solid-phase synthesis of PROTACs. Moreover, we examined the suitability of a polyethylene glycol (PEG) rather than an alkyl linker used in our previous study for synthesizing PROTACs. Facile and rapid solid-phase synthesis methods using the above E3 ligands for developing PROTACs targeting bromodomain-containing protein 4 (BRD4) were accomplished. Western blotting analysis revealed that minor differences in the E3 ligand and linker type significantly affected the activity of the synthesized PROTACs. Our solid-phase PROTAC synthesis methods enable rapid synthesis of multiple PROTACs with various combinations of ligands for the protein-of-interest and E3 ligands and linkers that connect these ligands.

Chest tube-free video-assisted thoracoscopic surgery secured by quantitative air leak monitoring: a case series.

Background: Although chest tube-omitted video-assisted thoracoscopic surgery (VATS) has been proven to be safe and efficacious, its universal application is precluded by a varying morbidity rate due to a lack of standardization. Since digital chest drainage has already shown improved accuracy and consistency in the management of postoperative air leak, we incorporated it in the strategy of intraoperative chest tube withdrawal, aiming to achieve better results. Methods: We collected the clinical data of 114 consecutive patients who underwent elective uniportal VATS pulmonary wedge resection at the Shanghai Pulmonary Hospital from May 2021 to February 2022. Their chest tubes were withdrawn intraoperatively after an air-tightness test facilitated by digital drainage: the end flow rate had to be kept ≤30 mL/min for >15 s at the setting of -8 cmH2O suctioning. The recordings and patterns of the air suctioning process were documented and analyzed as potential standards of chest tube withdrawal. Results: The mean age of the patients was 49.7±11.7 years. The mean size of the nodules was 1.0±0.2 cm. The location of the nodules encompassed all lobes, and 90 (78.9%) patients received preoperative localization. The postoperative morbidity and mortality rates were 7.0% and 0%, respectively. Six patients had clinically overt pneumothorax and two patients had postoperative bleeding that required intervention. All of the patients recovered on conservative treatment except for one case of pneumothorax that required additional tube thoracostomy. The median length of postoperative stay was 2 days; and the median time of suctioning, peak flow rate, and end flow rate were 126 s, 210 mL/min, and 0 mL/min, respectively. The median numeric rating scale for pain was 1 on postoperative day (POD) 1 and 0 on the day of discharge. Conclusions: Chest tube-free VATS assisted by digital drainage is feasible with minimal morbidity. Its strength of quantitative air leak monitoring produces important measurements for the prediction of postoperative pneumothorax and future standardization of the procedure.

Development of Rapid and Facile Solid-Phase Synthesis of PROTACs via a Variety of Binding Styles.

Optimizing linker design is important for ensuring efficient degradation activity of proteolysis-targeting chimeras (PROTACs). Therefore, developing a straightforward synthetic approach that combines the protein-of-interest ligand (POI ligand) and the ligand for E3 ubiquitin ligase (E3 ligand) in various binding styles through a linker is essential for rapid PROTAC syntheses. Herein, a solid-phase approach for convenient PROTAC synthesis is presented. We designed azide intermediates with different linker lengths to which the E3 ligand, pomalidomide, is attached and performed facile PROTACs synthesis by forming triazole, amide, and urea bonds from the intermediates.

Analysis of the Mechanism and Safety of Bisphosphonates in Patients with Lung Cancer and Bone Metastases.

OBJECTIVE: To explore the mechanism and safety of bisphosphonates in patients with lung cancer and bone metastases. METHOD: A total of 104 patients with lung cancer and bone metastases in our hospital were selected and randomly divided into two groups: control group (n = 54) and research group (n = 50). Chemotherapy was given to the control group, and the research group was treated with bisphosphonate drugs. The quality of life, HAMA, HAMD score, VAS score, treatment effect, serum calcium and KPS score, inflammatory factor levels, and immune function were compared between the two groups. RESULT: The quality of life in both groups was significantly increased (P < 0.05). The HAMA and HAMD scores of the research group decreased significantly than those of the control group after treatment (P < 0.05). The VAS scores of the two groups were significantly reduced (P < 0.05). The effective rates of treatment in the control group and the research group were 81.5% and 96.0%, respectively. Serum calcium was significantly decreased, and KPS score was significantly increased at weeks 1 and 6 after treatment, and the change was more obvious in the research group (P < 0.05). The levels of inflammatory factors in the two groups were significantly reduced, and the immune indicators were significantly increased. CONCLUSION: Bisphosphonates have good effect on patients with lung cancer and bone metastases, which can improve anxiety and depression, reduce pain score, improve serum calcium level and immune function, and reduce inflammatory response. Therefore, bisphosphonate drug therapy is worth widely used.

Development of Agonist-Based PROTACs Targeting Liver X Receptor.

Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily and function as ligand-dependent transcription factors that regulate cholesterol homeostasis, lipid homeostasis, and immune responses. LXR antagonists are promising treatments for hypercholesterolemia and diabetes. However, effective LXR antagonists and inhibitors are yet to be developed. Thus, we aimed to develop LXR degraders (proteolysis targeting chimeras PROTACs against LXR) as a complementary strategy to provide a similar effect to LXR inhibition. In this study, we report the development of GW3965-PEG5-VH032 (3), a PROTAC capable of effectively degrading LXRß protein. Compound 3 induced the ubiquitin-proteasome system-dependent degradation of the LXRß protein, which requires VHL E3 ligase. We hope that PROTACs targeting LXR proteins will become novel therapeutic agents for LXR-related diseases.