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.
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Source | J Pharmacol Sci (2014). Figure 1. AT-406 |
| Method | CCK-8 analysis | |
| Cell Lines | Hela cells and Siha cells | |
| Concentrations | 24 h | |
| 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 Experiment | |
|---|---|
| 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. |
| Concentrations | 0~3000 nM |
| Incubation time | 4 days |
| Animal Experiment | |
|---|---|
| Animal models | SCID mice (8–10 per group) bearing MDA-MB-231 xenograft model |
| Formulation | saline |
| Dosages | 10,30 and 100 mg/kg 5 days a week for 2 weeks |
| Administration | oral gavage |
| Molecular Weight | 561.71 |
| Formula | C32H43N5O4 |
| CAS Number | 1071992-99-8 |
| Solubility (25°C) | DMSO 85 mg/mL Ethanol 85 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| 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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