WEE1 kinase is a main regulator of the G2/M cell cycle checkpoint. It plays an important role in maintaining genomic stability by inhibiting CDK1 through a phosphorylation process at Tyr15. WEE1 is found to be overexpressed in several cancers and also act as a protective mechanism that allows cancer cells to repair DNA damage and survive under replicative stress. So, pharmacological inhibition of WEE1 has emerged as a promising therapeutic strategy. Many conventional chemotherapeutic agents act by inducing DNA damage, so it enables the activation of WEE1 in cancer cells to arrest the cell cycle and repair this damage by preventing cell death. Inhibition of WEE1 disrupts this protective checkpoint, which ultimately leads to mitotic catastrophe. Therefore, targeting WEE1 represents a promising and rational therapeutic approach, mainly in tumors with TP53 mutations. We have comprehensively discussed the structural features of WEE1, its regulation in DNA damage response, epigenetic control, and its role in cancer progression. We have also summarized the clinical development of major WEE1 inhibitors such as adavosertib, azenosertib (ZN-c3), and Debio 0123. Moreover, recently synthesized small-molecule inhibitors are also discussed with special focus on structure-activity relationship (SAR) insights, dual-target inhibitors, and PROTACs and molecular glue-based degraders. Two compounds, 8 and 11, were found to be the most potent WEE1 inhibitors with excellent enzymatic inhibition. This explains the importance of rational scaffold optimization and electron-withdrawing group insertion for enhanced activity. Overall, this review serves as a valuable reference for medicinal chemists in the development of next-generation WEE1 inhibitors. See also the graphical abstract(Fig. 1).
T cell activation is a central mechanism in adaptive immunity, modulating immune surveillance, host defense, and immune-mediated pathology. It is a highly coordinated mechanism including antigen recognition, co-stimulatory and co-inhibitory signaling, and cytokine-mediated regulation. This work aims to synthesize existing knowledge on the molecular mechanisms modulating T cell activation, with emphasis on integrated signaling cascades, experimental models, and therapeutic implications. A narrative review of the literature was conducted, focusing on key signaling cascades, regulatory mechanisms, and experimental methods used to analyze T cell activation in both basic and translational immunology. T cell activation is orchestrated via the mediation of T cell receptor (TCR) signaling with co-stimulatory and co-inhibitory cascades, alongside cytokine-mediated cues that collectively determine T cell fate and function. Critical intracellular signaling cascades, offer pivotal function in transcriptional and metabolic reprogramming. Experimental models such as in vitro stimulation systems, flow cytometry-based analyses, and advanced imaging approaches have significantly improved mechanistic knowledge of T cell responses. These insights have informed therapeutic approaches targeting T cell activation in cancer immunotherapy, autoimmune diseases, and infectious conditions. Although, obstacles in clinical translation remain. A comprehensive understanding of T cell activation needs integration of molecular, experimental, and clinical perspectives. Importantly, this review emphasizes the comparative strengths and limitations of contemporary experimental models and discusses how multi-omics integration and computational modeling can improve reproducibility, physiological relevance, and translational predictability in T cell research. Advancements in this field continue to offer opportunities for the development of targeted immunotherapies and enhanced disease intervention approaches. See also the graphical abstract(Fig. 1).
Type 1 diabetes (T1D), type 2 diabetes (T2D) and Alzheimer's disease (AD), which are heterogeneous multifactorial diseases, have become major global healthcare burdens and significant concerns for the future. Historically, the pathogeneses of these diseases were regarded as being largely distinct, but recent research suggests that this view is now outdated, with a lack of insulin and/or insulin resistance playing an important role in both forms of diabetes and AD. The current state of knowledge on the epidemiology, aetiology, and pathogenesis of T1D, T2D, and AD is summarised in this review. The evidence demonstrating overlapping pathological features between these diseases is also discussed here. Studies have demonstrated that islet autoimmunity, dysfunctional glucagon secretion, insulin resistance and islet amyloidosis manifest in both T1D and T2D. AD has been suggested to be type 3 diabetes (T3D), due to the associated abnormal brain insulin resistance, which is speculated to drive the progressive pathogenesis. Additionally, T1D and T2D are risk factors for AD and vice versa, and most AD patients also have diabetes or glucose intolerance, indicating bidirectional relationships. Thus, the association between AD and diabetes is already well established. Further understanding the connection between these diseases using recent scientific evidence may allow for the development of more efficient therapeutic strategies, which is highly desirable, given the prevalence of post-diagnosis complications. Evidence suggests that GLP-1R agonists can alleviate the phenotypes of all of these diseases, and these agonists could be used in the future to simultaneously treat them in subjects or prevent/delay their manifestation in at-risk individuals. See also the graphical abstract(Fig. 1).
