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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 |
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GDC-0152 is a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins with potential antineoplastic activity. |
| Birinapant
Birinapant (TL32711) is a bivalent Smac analogue, which is a potent antagonist of XIAP and cIAP1 with Kd values of 45 nM and less than 1 nM, respectively. Birinapant (TL32711) induces autoubiquitination and proteasome degradation of cIAP1 and cIAP2 in intact cells, resulting in the formation of RIPK1: Caspase-8 complex, which activates and induces tumor cell death. |
| BV6
BV6 is a small molecule Smac analog that antagonizes cIAP1 and XIAP. |
| LCL161
LCL161 is an orally bioavailable SMAC mimetic, potently binds to and inhibits multiple IAPs (i.e. XIAP, c-IAP). LCL161 enhanced the proapoptotic effects of nilotinib and PKC412, against leukemic disease in vitro and potentiated the activity of both kinase inhibitors against leukemic disease in vivo. |
| Embelin
Embelin is a cell-permeable benzoquinone compound that exhibits antitumor properties. Specifically antagonizes XIAP-mediated inhibition of caspase-9 activation by directly targeting the Smac and caspase-9 binding domain BIR3 (IC50 = 4.1 uM in a competitive binding assay with Smac peptide). |
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