MLN9708 is the prodrug of MLN2238 which is an inhibitor of the chymotrypsin-like proteolytic (β5) site of the 20Sproteasome with IC50 and Ki of 3.4 nM, 0.93 nM, respectively.
The proteasome is a highly sophisticated protease complex responsible for degradation of intracellular proteins. The proteasome collaborates with ubiquitin is the principal manner by which cells regulate protein homeostasis[3]. MLN9708 is a selective, potent, and reversible inhibitor of proteasome, and can be hydrolyzed to pharmacologically active ML2238, which inhibits the chymotrypsin-like β5 proteolytic site of the 20S proteasome with IC50 value of 3.4 nM. In addition, MLN2238 inhibits the caspase-like β1 and trypsin-like β2 proteolytic sites with IC50 values of 31 nM and 3.5 μM, respectively[4]. In vitro, MLN2238 strongly inhibited TNF-α-induced activation of the NF-κB pathway with EC50 value of 55 nM in HEK293 cells. MLN2238 can inhibit cell proliferation, including A375, H460, HCT116 and HT-29 cell lines, with LD50 values ranging in 4 – 58 nM, suggesting MLN9708 has potent anti-proliferative effect on lung and colon tumor[4]. MLN2238 predominantly inhibited chymotrypsin-like activity of the proteasome and induced accumulation of ubiquitinated proteins in Multiple Myeloma cells. MLN2238 inhibited growth and induces apoptosis in Multiple Myeloma cell lines MM.1S, INA-6, RPMI-8226, MM.1R, H929, OPM1, and OPM2 at concentration ranging 6.25 nM - 50 nM, suggesting that MLN9708 have activity of the against Multiple Myeloma cells[5]. In vivo, administered MLN2238 both intravenous injection at 14 mg/kg twice weekly or subcutaneous injection 4 mg/kg once daily showed strong antitumor activity and generated a greater apoptotic response in tumor tissue of CB17-SCID mice bearing WSU-DLCL2 xenografts[4]. Administered MLN2238 at 11 mg/kg via intravenous injection twice weekly for 3 weeks inhibited human Multiple Myeloma cell growth in vivo and prolongs survival in human plasmacytoma MM.1S xenograft mice model[6].
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