CH5138303 is an orally available Hsp90 inhibitor with Kd of 0.48 nM. CH5138303 showed high binding affinity for N-terminal Hsp90α (Kd=0.52nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50=0.098μM, NCI-N87 IC50=0.066μM) and also displayed high oral bioavailability in mice (F=44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition=136%).
|Cell lines||HCT116 and NCI-N87 cell lines|
|Preparation method||Culturing HCT116 cell line and NCI-N87 cell line according to the supplier’s instructions. Suspending cells in a medium are added to solutions which contains various concentrations of the test substance, and culturing the cells at 37 °C in 5% CO2. Four days later, adding cell Counting Kit-8 solution and measuring absorbance at 450 nm with Microplate-Reader iMark. Calculating antiproliferative activity by the formula (1−T/C) × 100 (%), where T represents the absorbance of drug-treated cells and C that of untreated control cells at 450 nm. Using Microsoft Excel 2007 to calculate the 50% inhibition concentration (IC50) values|
|Incubation time||4 days|
|Animal models||Mice with human NCI-N87 gastric cancer xenograft.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors.
Suda A, et al. Bioorg Med Chem. 2014 Jan 15;22(2):892-905. PMID: 24369839.
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Celastrol is a potent antioxidant and anti-inflammatory agent and a novel HSP90 inhibitor.
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