化合物信息

RDEA119 and Temsirolimus synergistically inhibit the growth of FTC133 xenograft tumors. After 2 weeks of treatment, the average tumor volume of the combination group is about 10% of control, 35% of Temsirolimus group and 20% of RDEA119 group, respectively. The average tumor weight of the combination group is 0.55 g, which is significantly smaller than that of control (2.90 g) and RDEA119 group (1.81 g), respectively. It is marginally smaller than that of the Temsirolimus group (1.15 cm³). ^[2] RDEA119 adiministrated at 6.25 mg/kg ( p.o. b.i.d., 5-day on, 2-day off) in combination with Rapamycin at 2 mg/kg (i.p. once weekly for 2-4 weeks) shows significant growth inhibition in all the 3 orthotopic primary pancreatic cancer xenografts, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein is inhibited to a greater extent with combination treatment in all the three models. ^[3] RDEA119 combined with Sorafenib is now under Phase I/II clinical trial? for the combination dose escalation study in advanced cancer patients.?

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For anchorage-dependent growth inhibition experiments, cells are plated in white 384-well plates at 1,000/20 μL/well or white 96-well microplates at 4,000/100 μL/well. After 24-h incubation at 37 °C, 5% CO₂, and 100% humidity, RDEA119 is incubated for 48 hours at 37 °C and assayed using CellTiter-Glo. For the 96-well anchorage-independent growth assay, wells of an “ultralow binding” plate (Corning) are filled with 60 μL of a 0.15% agarose solution in complete RPMI 1640. Then, 60 μL of complete RPMI 1640 containing 9,000 cells in 0.15% agarose are added per well. After 24 hour, 60 μL of a 3 × drug solution in agarose-free complete RPMI 1640 are added. After 7 d, 36 μL of 6 × 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium, inner salt reagent are added per well. After 2 hours at 37 °C, absorbance at 490 nm is determined on the M5 plate reader.