Mouse Double Minute 2 (MDM2) is an oncogene that contributes to the progression and metastasis of breast cancer and is associated with poor prognosis in breast cancer patients. SP-141 is a specific MDM2 inhibitor that directly binds to the MDM2 protein with a Ki value of 28±6nM in the FP-based assay and a KD value of 43 nM in the Biacore assay. SP-141 inhibited breast cancer cell growth (MCF-7/p53 wild-type, MCF-7/p53 knockdown, MDA-MB-468/p53 mutant, MDA-MB-231/p53 mutant, and MDA-MB-435/p53 mutant) with IC50 values ranging from 0.39 – 0.91μM. In MCF-7/p53 wild-type, MCF-7/p53 knockdown, and MDA-MB-468/p53 mutant cells, SP-141 at a concentration of 1μM increased apoptosis rate 14-, 7-, and 11-fold, respectively, relative to control cells. SP-141 also significantly induced cell cycle arrest in the G2 phase at a concentration of 0.5μM. The expression of cleaved PARP and Bax was increased, while that of Bcl-2 and Cyclin E was decreased in SP-141-treated breast cancer cells in a p53-independent manner. Intraperitoneal injection of SP-141 at a dose of 40mg/kg/day for 42 and 30 days inhibited tumor growth in nude mice bearing MCF-7 (by ~82%) and MDA-MB-468 (by ~80%) xenograft tumors, respectively.[1]
作用机制
SP-141 is a specific MDM2 inhibitor that shows a strong binding capacity for the MDM2 protein. The binding site of SP-141 is in the hydrophobic groove of MDM2. SP-141 destabilizes the MDM2 protein in vitro by promoting its ubiquitination.[1]
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