Z-IETD-FMK

Z-IETD-FMK (Z-IE(OMe)TD(OMe)-FMK) is a selective and cell permeable caspase-8 inhibitor^[1]. Z-IETD-FMK is also a granzyme B inhibitor^[5]. In Vitro: Z-IETD-FMK causes full inhibition only of the proapoptotic effect of TNFα with an IC₅₀ of 0.46 μM^[1]. Z-IETD-FMK and Z-VAD-FMK at non-toxic doses are found to be immunosuppressive and inhibit human T cell proliferation induced by mitogens and IL-2. They are shown to block NF-κB in activated primary T cells, but have little inhibitory effect on the secretion of IL-2 and IFN-γ during T cell activation^[2]. Z-IETD-FMK inhibits the cleavage of caspase-8 and only partially inhibits the cleavage of caspase-3 and PARP. Z-IETD-FMK can prevent the execution of apoptosis in retinal cells exposed to different apoptotic stimuli^[3]. In Vivo: Pharmacological inhibition of caspase-8 by z-IETD-FMK robustly reduces tumour outgrowth and this is closely associated with a reduction in the release of pro-inflammatory cytokines, IL-6, TNF-α, IL-18, IL-1α, IL-33, but not IL-1β. Furthermore, inhibition of caspase-8 reduces the recruitment of innate suppressive cells, such as myeloid-derived suppressor cells, but not of regulatory T cells to lungs of tumour-bearing mice^[4].