MARK4 (Microtubule Affinity Regulating Kinase 4)

The treatment with JMI-1094 significantly decreased the colonization and cell migration potential of MCF-7 and A549 cell lines, and induced apoptosis. These findings suggest JMI-1094 as a promising MARK4 inhibitor with potential future therapeutic implications in MARK4-mediated cancer(s).

The study developed a novel signature based on genes dynamically expressed during malignant AT2 cell dedifferentiation, capable of predicting the prognosis of LUAD patients, and offered four accurate prognostic biomarkers (ADM, MARK4, PARVA, and RPS6KA1).

FTO or MARK4 inhibition suppresses HARP synthesis and increases apoptosis after various stresses, including chemotherapy. γ-tubulin, FTO, and MARK4 are therapeutic targets, as they comprehensively promote HARP translation, a potential Achilles' heel for cancer's resistance to physiologic or therapeutic stress.

Enzyme inhibition assays estimated Harmane's IC50 (half-maximal inhibitory concentration) value as 2.72 µM against MARK4, while fluorescence spectroscopy measured a binding constant (Ka) of 0.1 × 105 M- 1. These results strengthen the idea that Harmane can be a potent MARK4 inhibitor, offering therapeutic promise for neurodegenerative diseases and cancer.

Fluorescence binding assays revealed a strong binding affinity (K = 2.8 × 106 M-1). The findings of our study establish syringic acid as a potent MARK4 inhibitor, providing a perfect platform for its use in tackling MARK4-associated diseases.

These results position apigenin as a potent inhibitor of MARK4, offering a dual therapeutic advantage-both as an anti-cancer agent and as a neuroprotective compound for the potential treatment of AD. This study opens new avenues for the development of apigenin-based therapeutics targeting kinase dysregulation in cancer and neurodegeneration.

Notably, p-Y42 RhoA and PKM2 co-immunoprecipitated with β-catenin and YAP. Based on these findings, we proposed a novel mechanism by which p-Y42 RhoA and PKM2, in conjunction with β-catenin and YAP, regulate PGK1 expression, contributing to the progression of glioma upon EGF.

MARK4 expression was upregulated in GC and promoted the proliferation, migration, and invasion of GC cells through the MAPK/ERK pathway.

Molecular dynamics simulations were conducted for all six drugs, with donepezil serving as the control drug. Based on the findings from molecular dynamics simulations and the MMGBSA analysis, it can be inferred that citalopram and mirtazapine exhibit considerable potential as anti-depressant agents. Consequently, these compounds warrant further investigation through in vitro and in vivo investigations in the context of treating AD.

Interestingly, VI-9 induces apoptosis and decreases the metastatic potential of the C3A and SNU-475 cell lines. The present work opens a newer avenue for vanillin-isatin hybrids and their derivatives in developing MARK4-targeted anticancer therapies.

Molecular docking, cell cytotoxicity, mitochondrial reactive oxygen species measurement and oxidative DNA damage were also studied to understand the mechanism of action of the molecules on cancer cells. It was found that the designed and synthesized compounds played anti-cancer roles by binding and inhibiting MARK4 protein.

the multi-spectroscopic, molecular docking and MD simulation studies were performed to analyse the conformational changes, binding studies, intermolecular interactions, and stability of MARK-4 protein upon binding 5-FU. This demonstrates that NF can enhance the effectiveness of anticancer drugs.Communicated by Ramaswamy H. Sarma.