Ubiquitination plays an essential role in human cancers. EOAI3402143 is a deubiquitinase inhibitor that reduces the activity of deubiquitinase Usp5 and Usp9x in both vemurafenib sensitive and resistant A375 melanoma cells. Incubation of A375R cells with 2μM EOAI3402143 for 8 hours reduced the levels of pERK, pStat3, and increased the concentration of NOXA.[1] Treatment of pancreatic cancer patient-derived cell lines (UM-2, UM-6, UM-16, and UM-76) with EOAI3402143 (1-5μM) suppressed cell survival in a dose-dependently manner. EOAI3402143 at a concentration of 600nM completely suppressed UM-2 3D colony growth compared with the vehicle-treated controls. Treatment with 600nM EOAI3402143 also promoted the 3D colony growth of 8041 cells by two folds. In both human MIAPACA2 xenografts and mouse 8041 xenografts, administration with EOAI3402143 at 15mg/kg for 12 days effectively inhibited the activity of Usp9x in tumors. However, tumor suppression was only observed in human MIAPACA2 xenografts. [2] In NSH mice inoculated with A375 cells, treatment with EOAI3402143 at both 7.5 and 15mg/kg completely suppressed tumor growth.[1]
作用机制
EOAI3402143 is a small molecule deubiquitinase inhibitor that retains potent inhibitory activity against Usp5 and Usp9x.[1]
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