生物活性

• 描述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]

• 动物研究
  剂量	Mice: 25 mg/kg - 200 mg/kg[2] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Dose 50 mg/kg Administration p.o. Cmax 15.5 μg/ml T1/2 8.8 h AUClast 251.2 μg·h/ml

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00559533	Neoplasms	Phase 1	Completed	-	United States, Colorado ... more >> Aurora, Colorado, United States, 80045 United States, Massachusetts Boston, Massachusetts, United States, 02115 United States, New York New York, New York, United States, 10065 United States, Texas Houston, Texas, United States, 77030 San Antonio, Texas, United States, 98229 France Bordeaux, France, 33076 Lyon, France, 69373 Collapse <<
  NCT01970930	-	-	Completed	-	United States, New York ... more >> Icahn School of Medicine at Mount Sinai New York, New York, United States, 10029 Collapse <<
  NCT00623870	Hematologic Neoplasms	Phase 1	Completed	-	United States, California ... more >> Duarte, California, United States, 91010 United States, New Jersey New Brunswick, New Jersey, United States, 08901 United States, New York New York, New York, United States, 10065 United States, Texas Houston, Texas, United States, 77030 Canada, Ontario Toronto, Ontario, Canada, M5G 2M9 Canada, Quebec Montreal, Quebec, Canada, H3T 1E2 Italy Bologna, Emilia-Romagna, Italy, 40138 Roma, Lazio, Italy, 00161 United Kingdom Glasgow, United Kingdom, G12 0YN Leeds, United Kingdom, LS9 7TF Oxford, United Kingdom, OX3 7LJ Collapse <<

• 参考文献

• [1] Vu B, Wovkulich P, et al. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. ACS Med Chem Lett. 2013 Apr 2;4(5):466-9.

  [2] Tovar C, Graves B, et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 2013 Apr 15;73(8):2587-97.