AT-406 (formerly known as SM-406) is a novel and orally active antagonist of multiple IAP proteins. AT-406 selectively inhibits the biological activity of IAP proteins, including X chromosome-linked IAP (XIAP), the cellular IAPs 1 (c-IAP1) and 2 (c-IAP2) and melanoma inhibitor of apoptosis protein (ML-IAP). AT-406 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay. AT-406 induced apoptosis is correlated with its ability to down-regulate XIAP whereas AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistance cell lines. AT-406 is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Additionally, AT-406 enhances the carboplatin-induced ovarian cancer cell death and increases survival of the experimental mice in vivo. AT-406 is currently in phase I clinical trials for the treatment of human cancer.
|Source||J Pharmacol Sci (2014). Figure 1. AT-406|
|Cell Lines||Hela cells and Siha cells|
|Incubation Time||5 or 10 μM|
|Results||The results of CCK-8 analysis showed that AT-406 cell inhibition was less than 20% at these concentrations. Under normoxic and hypoxic conditions, Hela cells treated with AT-406 at 10 μM prior to irradiation showed a significant survival curve shift with SERs of 1.81 and 2.07, respectively, compared with untreated Hela cells|
|Cell lines||MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines|
|Preparation method||The MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines were purchased from the American Type Culture Collection (ATCC). Cells were seeded in 96-well flat bottom cell culture plates at a density of 3–4×103 cells/well with compounds and incubated for 4 days. The rate of cell growth inhibition after treatment with different concentrations of the inhibitors was determined by assaying with (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium mono-sodium salt. WST-8 was added to each well to a final concentration of 10%, and then the plates were incubated at 37°C for 2–3 h. The absorbance of the samples was measured at 450 nm using a TECAN ULTRA Reader. Concentration of the compounds that inhibited cell growth by 50% (IC50) was calculated by comparing absorbance in the untreated cells and the cells treated with the compounds.|
|Incubation time||4 days|
|Animal models||SCID mice (8–10 per group) bearing MDA-MB-231 xenograft model|
|Dosages||10,30 and 100 mg/kg 5 days a week for 2 weeks|
|Solubility (25°C)||DMSO 85 mg/mL
Ethanol 85 mg/mL
Powder -20°C 3 years ; 4°C 2 years
In solvent -80°C 6 months ; -20°C 1 month
|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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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