| 名稱 | RG7112 |
| 描述 | RG7112 (RO5045337) (RO5045337) is an orally bioavailable and selective p53-MDM2 inhibitor. |
| 細(xì)胞實(shí)驗(yàn) | Cell lines: Three wild-type p53 (HCT116,RKO,and SJSA1) and 2 mutant p53 (SW480 and MDA-MB-435) cell lines. Concentrations: ~5 μM. Incubation Time: 5 d. Method: Cell proliferation/viability is evaluated by the tetrazolium dye (MTT) assay.Cell growth kinetics are measured using the IncuCyte live cell imaging system.For cell-cycle analysis,cells are cultured in T75 flask with appropriate growth medium (106 cells/condition in 10 mL) and incubated overnight at 37°C.They are incubated with test compounds and processed. |
| 激酶實(shí)驗(yàn) | HTRF assay: Homogeneous time-resolved fluorescence (HTRF) assay measures the signal generated by 2 components when they are in close proximity. The p53–MDM2 binding assay uses a biotinylated peptide derived from the MDM2-binding domain of p53 and a truncated N-terminal portion of recombinant human GST-tagged MDM2 protein containing the p53-binding domain. Proteins for crystal structure studies are expressed in E. coli strain BL21 using the helper plasmid pUBS 520 coding for the lacIq repressor and the rare tRNAArg [AGA/AGG]. For crystallization, the frozen protein is thawed and concentrated to 9.8 mg/mL using a Centricon concentrator (3,000 MW cutoff). The complex is then formed by combining the protein with a slight molar excess of the inhibitor (stock solution is 100 mM in DMSO) and this solution is allowed to sit for 4 hours at 4°C. Cryopreserved crystals are used to collect diffraction data on beamline X8C at the National Synchrotron Light Source at Brookhaven National Laboratory. |
| 動(dòng)物實(shí)驗(yàn) | Animal Models: Nude mice bearing SJSA-1,MHMn,or LNCaP xenografts. Formulation: Suspended in 1% Klucel LF/0.1% Tween 80. Dosages: ~200 mg/kg. Administration: p.o. |
| 體外活性 | In three wild-type p53 (HCT116, RKO, and SJSA1) cell lines, RG7112 selectively and dose-dependently inhibits cell growth. In cancer cells expressing wild-type p53, RG7112 activates the p53 pathway, and induces cell-cycle arrest and apoptosis. RG7112, both alone and combined with Peg-IFNα 2a, significantly decreases MPN colony-forming unit-granulocyte macrophage and burst-forming unit-erythroid numbers and preferentially eliminates the total number of JAKV617F(+) MPN hematopoietic progenitor cells. In addition, in MDM2-amplified liposarcoma cells, RG7112 significantly synergizes with Trabectedin. |
| 體內(nèi)活性 | In rats, RG7112 impairs thrombopoiesis via activation of p53. In the SJSA1 xenograft mouse model, RG7112 (200 mg/kg, p.o.) penetrates tumor cells and activate p53 and its 2 major functions, cell-cycle arrest and apoptosis. In nude mice bearing SJSA-1, and MHMn xenografts, RG7112 (100 mg/kg, p.o.) causes tumor regression. |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : 93 mg/mL (128 mM)
DMSO : 93 mg/mL (128 mM)
H2O : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | E1 activating enzyme | Inhibitor | E1/E2/E3 Enzyme | Ubiquitin conjugating enzyme | Ubiquitin activating enzyme | E3 ligating enzyme | MDM-2/p53 | Ubiquitin ligase | RG7112 | E2 conjugating enzyme | RO 5045337 | inhibit | RO-5045337 |
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