MDM2 is a negative regulator of p53 which can directly bind to p53, inhibit the transcriptional activity of p53 and target p53 for degradation by the proteasome. This makes restoration of p53 activity by inhibiting the p53-MDM2 interaction to represent a novel approach to cancer treatment. RG7112 is the first clinical small-molecule MDM2 inhibitor currently in Phase I clinical studies with IC50 value of 18nM in HTRF assay. RG7112 inhibited 5-day proliferation with IC50 values ranging in 0.18−2.2 μM in cell lines expressed wild-type p53, but with IC50 values ranging in 5.7−20.3μM in cell lines expressed p53 mutation[1]. Treatment with RG7112 could activate p53 signaling and dose dependently accumulate p53 protein and its targets, MDM2 and p21 in SJSA1 osteosarcoma cells expressing wild-type p53. RG7112 induced cell-cycle arrest and apoptosis in SJSA1 osteosarcoma cells with EC50 values of 0.4μM and 1μM, respectively. And inhbition of caspase by Z-VAD-FMK activity does not affect the kinetics of cell death induced by RG7112[2]. Daily oral administration of RG7112 inhibited tumor growth by 74% at dose of 50 mg/kg and achieved tumor regression at dose of 100 mg/kg in nude mice xenograft human osteosarcoma cell line SJSA-1 over-expressing MDM2 protein due to its MDM2 gene amplification[1].
作用机制
RG7112 can occupy the p53-binding pocket of MDM2mimicking the interactions of critical p53 amino acid residues and block its interactions with p53.[1][2]
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