WCY-8-67 is a potent, selective inhibitor of deubiquitinating enzyme (DUB) USP5 with IC50 of 0.33 uM and SPR Kd of 5.73 uM, inhibits the growth of t(8;21) AML cells.
WCY-8-67 is seletive over a panel of 35 recombinant human DUB proteins in enzyme assays.
WCY-8-67 inhibits the deubiquitinating activity of USP5 by binding to the UBA2 region.
WCY-8-67 inhibits AML cell proliferation and induces differentiation of AML cells in vitro, shows antiproliferative effects on AE-positive AML cells (Kasumi-1, Skno-1, and U937-AE cells) with IC50 of 1.75 uM, 0.99 uM and 1.20 uM respectively, with negligible antiproliferative effects on other AE-negative AML cells.
WCY-8-67 induces ubiquitination-mediated degradation of AE protein in both USP5WT and USP5C335A mutant cells.
WCY-8-67 suppresses colony formation and decreases the proportion of LSCs, resulting in AML cell differentiation.
WCY-8-67 down-regulates the expression of MDM2 and up-regulate the expression of p53 in two AML cell lines in a dose-dependent manner.
WCY-8-67 (20 mg/kg, ip, qd) inhibits AML progression in Skno-1 subcutaneous xenograft mouse model. WCY-8-67 inhibits USP5 through formation of insoluble aggresomes.