The p38 mitogen-activated protein kinase (p38MAPK) pathway has been implicated in a variety of pathological conditions including inflammation and metastasis. Post-transcriptional regulation of genes harboring adenine/uridine-rich elements (AREs) in their 3′-untranslated region (3′-UTR) is controlled by MAPK-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of the p38MAPK. In response to diverse extracellular stimuli, MK2 influences crucial signaling events, regulates inflammatory cytokines, transcript stability and critical cellular processes. Expression of genes involved in these vital cellular cascades is controlled by subtle interactions in underlying molecular networks and post-transcriptional gene regulation that determines transcript fate in association with RNA-binding proteins (RBPs). Several RBPs associate with the 3′-UTRs of the target transcripts and regulate their expression via modulation of transcript stability. Although MK2 regulates important cellular phenomenon, yet its biological significance in tumor progression has not been well elucidated till date. In this review, we have highlighted in detail the importance of MK2 as the master regulator of RBPs and its role in the regulation of transcript stability, tumor progression, as well as the possibility of use of MK2 as a therapeutic target in tumor management.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer in the world and the most prevalent cancer of developing countries. Increased disease burden and a smaller number of approved targeted therapies are a growing concern worldwide. Isoindolinone motifs have been a central part of many pharmacological compounds, and their derivatives possess substantial anticancer potential. However, their anticancer potential against HNSCC has not been well investigated. In the current study, a series of 3-methyleneisoindolinones have been designed and synthesized and their late-stage intramolecular Heck cyclization was achieved to evaluate their anticancer potential against HNSCC cells. Additionally, in silico ADME profiling of synthesized compounds revealed their drug-likeness properties as potential drug candidates. Among the synthesized compounds, 3-bromo-5-methylpyridin-2-yl-3-methyleneisoindolin-1-one, i.e., 3n, with a pyridyl unit exhibited the most significant cytotoxicity against HNSCC cells. The cytotoxic potential of synthesized compounds varied depending on the nature of substituents present and has been well established with structure-activity relationship studies. Further, flow cytometric analysis showed that 3f, 3h, and 3n triggered intracellular oxidative stress, disrupted mitochondrial membrane potential, and interrupted the cell cycle of HNSCC cells in the S-phase and sub-G1 phase. Further, 3f, 3h, and 3n also exhibited pro-apoptotic potential and induced cellular apoptosis in the HNSCC cells. Overall, the findings of this study attributed 3-methyleneisoindolinone chemistry and efficacy evaluation and corroborated their anticancer potential against HNSCC. It will pave the way to further design and optimize novel 3-methyleneisoindolinone as effective antitumor agents, which may provide effective treatment modalities against HNSCC.