PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer.

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.

DMF as an amine source: iron-catalyzed cyclization of 2H-azirines to imidazoles.

A novel method has been developed for the synthesis of 1-methyl-4,5-diaryl-1H-imidazoles through Fe(II)-catalyzed cyclization of 2H-azirines and N,N-dimethylformamide (DMF) as an amine source. This transformation involves the cleavage of C-N and CN double bonds and the construction of new C-N and CN double bonds. The reaction has readily available starting materials, a wide range of substrates and mild reaction conditions. In addition, the reaction also facilitated the convenient synthesis of 1-methyl-2,4,5-triaryl-1H-imidazoles.

Design, synthesis, and evaluation of BTK-targeting PROTACs with optimized bioavailability in vitro and in vivo.

Ibrutinib is a first-line drug for the treatment of B-cell malignancies. BTKC481S mutation has led to drug resistance during clinical application. Herein, a novel BTK-targeting PROTAC molecule with better solubility and bioavailability was developed. Compound 15-271 has better solubility than ibrutinib and some reported BTK PROTACs. 15-271 has better liver microsomal stability than its analogues in multiple species. More importantly, 15-271 has a longer half-life and better bioavailability in vivo. The development strategy of compound 15-271 can be a general procedure for the optimization of other PROTACs.

Phospholipid-Membrane-Based Nanovesicles Acting as Vaccines for Tumor Immunotherapy: Classification, Mechanisms and Applications.

Membrane vesicles, a group of nano- or microsized vesicles, can be internalized or interact with the recipient cells, depending on their parental cells, size, structure and content. Membrane vesicles fuse with the target cell membrane, or they bind to the receptors on the cell surface, to transfer special effects. Based on versatile features, they can modulate the functions of immune cells and therefore influence immune responses. In the field of tumor therapeutic applications, phospholipid-membrane-based nanovesicles attract increased interest. Academic institutions and industrial companies are putting in effort to design, modify and apply membrane vesicles as potential tumor vaccines contributing to tumor immunotherapy. This review focuses on the currently most-used types of membrane vesicles (including liposomes, bacterial membrane vesicles, tumor- and dendritic-cell-derived extracellular vesicles) acting as tumor vaccines, and describes the classification, mechanism and application of these nanovesicles.

Treatment of Pediatric Intercondylar Humerus Fracture With External Fixation and Percutaneous Pinning After Closed Reduction.

Background: It is uncommon for young children to suffer an intercondylar fracture of the distal humerus. Although many approaches have been described to manage, there is no specific and accepted treatment protocol for such fracture patterns. This study aimed to identify the incidence of intercondylar fracture of the distal humerus in the pediatric population and report the clinical outcome of external fixation and percutaneous pinning in such injury patterns. Methods: Pediatric patients under the age of 14 years who had an intercondylar fracture of the distal humerus treated with external fixation and percutaneous pinning between January 2013 and December 2018 at the author's Wuhan Union Hospital were retrospectively evaluated. The detailed baseline information of the patients, operating time, time to union time, and carrying angle difference (CAD) of the injured extremity were collected. During the follow-up visit, clinical results were evaluated using the Mayo Elbow Performance Score (MEPS) and the Flynn criteria. Results: A total of eight patients (2 women and 6 men) with an average age of 8 years (5-12 years) who had an intercondylar fracture of the distal humerus (1 C2 and 7 C1) were included. All the patients achieved union, and the average MEPS score was 95 points 24 months after the surgery. Conclusion: The intercondylar fracture of the distal humerus in children is rare, and closed reduction and external fixation is a viable treatment option, especially for the C1 type of fracture pattern.

Engineered extracellular vesicles: potentials in cancer combination therapy.

Extracellular vesicles (EVs) are a group of secretory vesicles with cell-derived membrane and contents. Due to the cargo delivery capability, EVs can be designed as drug delivery platforms for cancer therapy. Biocompatibility and immune compatibility endow EVs with unique advantages compared with other nanocarriers. With the development of this field, multiple ingenious modification methods have been developed to obtain engineered EVs with desired performance. Application of engineered EVs in cancer therapy has gradually shifted from monotherapy to combinational therapy to fight against heterogeneous cancer cells and complex tumor microenvironment. In addition, the strong plasticity and load capacity of engineered EV make it potential to achieve various combinations of cancer treatment methods. In this review, we summarize the existing schemes of cancer combination therapy realized by engineered EVs, highlight the mechanisms and representative examples of these schemes and provide guidance for the future application of engineered EVs to design more effective cancer combination treatment plans.

Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein-mediated lipogenesis.

BACKGROUND AND AIMS: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. APPROACH AND RESULTS: Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated Ldlr-/- mice, and reduces the formation of cholesterol crystals and associated crown-like structures of Kupffer cells. Notably, 25-HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25-HL shows a good safety and pharmacokinetics profile. CONCLUSIONS: This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.

Interleukin -1ß Promotes Lung Adenocarcinoma Growth and Invasion Through Promoting Glycolysis via p38 Pathway.

BACKGROUND: There is a close relationship among inflammation, glycolysis, and tumors. The IL-1 family includes important inflammatory cytokines, among which IL-1ß has been widely studied. In this study, we focused on the effect of IL-1ß on glycolysis of lung adenocarcinoma (LUAD) cells in vivo and in vitro and explored its possible mechanisms. METHODS: A bioinformatic database and quantitative real-time PCR were used to analyze the expression of glycolysis-related enzyme genes and their correlations with IL1ß in human LUAD samples. The human LUAD cell line A549 and Lewis lung carcinoma LLC cell line were stimulated with IL-1ß. In vitro treatment effects, including glycolysis level, migration, and invasion were evaluated with a glucose assay kit, lactate assay kit, Western blotting, wound healing, and the transwell method. We established a mouse model of subcutaneous tumors using LLC cells pretreated with IL-1ß and analyzed in vivo treatment effects through positron-emission tomography-computed tomography and staining. Virtual screening and molecular dynamic simulation were used to screen potential inhibitors of IL-1ß. RESULTS: Our results showed that IL1ß was positively correlated with the expression of glycolysis-related enzyme genes in LUAD. Glycolysis, migration, and invasion significantly increased in A549 and LLC stimulated with IL-1ß. In vivo, IL-1ß increased growth, mean standard uptake value, and pulmonary tumor metastasis, which were inhibited by the glycolysis inhibitor 2-deoxy-D-glucose and p38-pathway inhibitors. Small molecular compound ZINC14610053 was suggested being a potential inhibitor of IL-1ß. CONCLUSION: IL-1ß promotes glycolysis of LUAD cells through p38 signaling, further enhancing tumor-cell migration and invasion. These results show that IL-1ß links inflammation to glycolysis in LUAD, and targeting IL-1ß and the glycolysis pathway may be a potential therapeutic strategy for lung cancer.

Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.

A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.

Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors.

Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.