2024/2/2

WIKIMOLE—Z-VAD (OMe)-FMK & Z-VAD (OH)-FMK

Z-VAD (OMe)-FMK and Z-VAD (OH)-FMK are both caspase inhibitors.

Z-VAD (OMe)-FMK is the methyl ester form of this inhibitor, and the methoxy group makes it permeable. Z-VAD (OH)-FMK (also known as Z-VAD-FMK) is the carboxylic acid form of this inhibitor, and the hydroxy group gives it some water solubility.

Mechanism of Action

Z-VAD (OMe)-FMK and Z-VAD (OH)-FMK are both caspase inhibitors, but the differences in their chemical structures lead to distinct properties and modes of action. Z-VAD (OMe)-FMK is a cell-permeable, irreversible caspase inhibitor that can inhibit caspases and apoptosis in tumor cells in vitro. The methyl ester compound undergoes hydrolysis by endogenous esterase activity upon entering the cell, generating the biologically active form. Therefore, pre-treatment with esterase is required when using it with isolated, purified, or recombinant caspases. On the other hand, Z-VAD (OH)-FMK is a carboxylic acid compound that can be directly added to cell culture media without the need for esterase pre-treatment.

Biological Applications

Z-VAD-FMK, as a broad-spectrum inhibitor of Caspase, plays a crucial role in apoptosis research. Numerous preclinical studies, both in vitro and in vivo, indicate that Caspase primarily acts as an inflammatory and apoptotic mediator in various pathologies. Consequently, several Caspase inhibitors have been patented for their anti-inflammatory and apoptotic functions. However, due to factors such as drug toxicity, their application is currently limited to preclinical research. Although some studies propose novel therapeutic approaches using nanoparticle delivery systems and CRISPR/Cas9 gene editing to improve drug delivery and reduce drug-induced toxicity, targeting individual Caspases separately, these remain short-term solutions. Because the lack of Caspase activity can increase the crosstalk between cell death and inflammatory pathways, there are concerns about the long-term efficacy of Caspase inhibitors. If inhibitors increase the risk of cell death and inflammatory reactions, they may exacerbate diseases. Therefore, it is crucial to clearly determine the specific mechanisms of action of Caspase inhibitors in preclinical models.