Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models.

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein ß-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.

Associations of Job Insecurity With Perceived Work-Related Symptoms, Job Satisfaction, and Turnover Intentions: The Mediating Role of Leader-Member Exchange and the Moderating Role of Organizational Support.

This study wants to examine effects of job insecurity on several work-related outcomes (perceived work-related symptoms, job satisfaction, and turnover intentions) by developing a moderated mediation model. The model emphasizes the role played by the quality of leader-member exchange (LMX) in mediating the relation between perceived job insecurity and outcomes related to work, and the moderating role of perceived organizational support (POS) in influencing the mediation. Survey data from 510 workers at Italian organizations were collected, and regression was used to evaluate the hypotheses. After age, gender, education, and organizational tenure were controlled, results showed that perceived quality of LMX carried the effect of job insecurity on all outcomes, and that this relationship was stronger for employees who reported higher levels of POS. This study makes important theoretical and practical contributions to job insecurity, LMX, and POS research, underlining the importance of promoting the leader-member relationship's quality in an ethical and supportive work environment.