Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins.

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC50 = 0.009 µM, 0.49 µM and 3.24 µM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 µM and 0.63 µM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

Reliability and validity of the Chinese version of the spiritual health scale.

BACKGROUND: In recent years, spiritual health became a focus of interest and nurses' spiritual health is crucial to the quality of their own lives and patients' health care. In China, high workloads, tense nurse-patient relationships, and low social status have been found to have negative impacts on the work attitude and nursing quality and spiritual health offers direction for solving this problem. This study assessed the spiritual health levels of nurses on the Chinese mainland using a revised Chinese version of the spiritual health scale (SHS-C). METHODS: A total of 747 nurses were recruited in Zhejiang Province, China. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of the revised SHS-C were performed using convenience sampling, with 291 and 456 nurses used for each analysis type, respectively. Items on the SHS-C were screened using the discrete trend method, the extreme group approach, correlation analysis, and EFA to create a revised mental health questionnaire for nurses. An internal consistency test and CFA were then performed to verify the spiritual health questionnaire for nurses. A self-reporting questionnaire consisting of demographic questions and the revised SHS-C items was used for this cross-sectional correlation study. RESULTS: The revised SHS-C included 6 subscales comprising a total of 28 items. Cronbach's α and retest reliability for the revised questionnaire were 0.90 and 0.73, respectively. The fit of the model was analyzed by CFA [χ2/df =1.79; goodness of fit index (GFI) =0.83; adjusted GFI (AGFI) =0.79; root mean square error of approximation (RMSEA) =0.06; normed fit index (NFI) =0.86; comparative fit index (CFI) =0.93; non-NFI (NNFI) =0.92; incremental fit index (IFI) =0.93; parsimony NFI (PNFI) =0.76; parsimony CFI (PCFI) =0.83; and parsimony GFI (PGFI) =0.69; with each index score higher than those of the 5-subscale SHS short form previously developed by Hsiao et al.]. A reliability test showed that the overall Cronbach's α was 0.93, with a Cronbach's α of between 0.82 and 0.92 for each section. This study developed and validated a revised SHS-C. CONCLUSIONS: Our research will help policymakers, administrators, nursing leaders, and educators to identify areas for improvement regarding nurses' spiritual health, which could translate into significant improvements in patients' health care.