Deubiquitinase

384.27

DMSO 77 mg/mL (200.37 mM)
Ethanol 18 mg/mL (46.84 mM)
Water Insoluble

WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells. WP1130 is more effective in inducing apoptosis of myeloid and lymphoid tumor cells (IC50 0.5 to 2.5 μM) than normal CD34+ hematopoietic precursors, dermal fibroblasts, or endothelial cells (IC50 ~5 to 10 μM). WP1130 reduces Bcr/Abl protein levels through a unique mechanism that is not affected by mutations that interfere with imatinib mesylate binding. WP1130 inhibits phosphorylation of both the wild-type and the T315I mutant Bcr/Abl proteins, as demonstrated by the rapid disappearance (within 1 hour) of phosphotyrosyl-Bcr/Abl in both BV173 and BV173R cells. WP1130-induced down-regulation of Bcr/Abl is accompanied by apoptosis of CML cells. Treatment with WP1130 yields an anti-proliferative effect across all cell lines tested in a dose-dependent manner. Notably, treatment with WP1130 results in marked anti-proliferative activity and morphological changes in NCH644 and NCH421K glioma stem-like cells. Treatment with WP1130 results in a dose-dependent and probably compensatory increase of Mcl-1 mRNA levels after 6 h and only a minor decrease after 24 h. Similar findings are observed for Usp9X levels. These data suggest that WP1130 down-regulates Mcl-1 and Usp9X through a post-transcriptional mechanism.

WP1130 suppresses the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. To assess the possible therapeutic activity of WP1130 against CML, nude mice received a subcutaneous transplant with K562 cells and are treated with 30 mg/kg WP1130 every other day for 9 days after palpable tumor formation (10 days). This dose and schedule are well tolerated and effective in other tumor models. Antitumor activity is compared with that after daily Imatinib mesylate treatment (50 mg/kg). Nineteen days after tumor inoculation, tumors in the control group reached maximum allowable dimension, and the effect of therapy is assessed. WP1130 treatment suppresses K562 tumor growth to an extent comparable to that observed in imatinib mesylate-treated animals, suggesting that WP1130 is active in reducing the growth of established K562 tumors.

WP1130; WP 1130; WP-1130

C₁₉H₁₈BrN₃O

856243-80-6