GDC-0152 is a small-molecule IAP antagonist that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. GDC-0152 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. GDC-0152 induces activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity.
|Cell lines||MDA-MB-231, mormal HMECs cell lines|
|Preparation method||Cell Viability and Caspase Activation Assays Human breast carcinoma MDA-MB-231 were obtained from ATCC. Normal human mammary epithelial cells (HMECs) were obtained from Cambrex Corp.. Cells were dissociated from tissue culture flasks by incubation with Accutase® (Innovative Cell Technology Inc.) for 5–10 minutes. Detached cells were washed with phosphate-buffered saline (PBS) and were resuspended in assay media (MDA-MB-231 cells: RPMI1640 supplemented with 10% fetal bovine serum [Sigma-Aldrich] and 2 mM L-glutamine [GlutaMAX-1; Gibco/Invitrogen Corp.]) or culture media (HMECs: MEBM® with MEGM SingleQuots® provided by Cambrex Corp.). Cells were placed in tissue culture-treated, white-wall (Corning, Inc.) or black-wall (PE Biosystems), clear-bottom, 96-well plates at 1 × 104 cells/well in a volume of 50 μL. The plates were incubated at 37°C and 5% CO2 overnight, the media was removed, and 1 or it's enantiomer were added in assay media. Cells cultured in white-wall, clear-bottom plates were incubated at 37°C and 5% CO2 for 3 days before cell viability was measured using the CellTiter-Glo® luminescent cell viability assay kit (Promega Corp.) according to the manufacturer's instructions. Cells seeded in black-wall, clear-bottom plates were incubated at 37°C and 5% CO2 for 3–24 hours before caspase-3 and -7 homogeneous activities were assessed using the Apo-ONE® caspase-3/7 assay kit (Promega Corp.) according to the manufacturer's instructions.|
|Incubation time||3 days|
|Animal models||Human breast cancer MDA-MB-231 cells tumor xenograft mice|
|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.
|Solubility||DMSO 90 mg/mL
Ethanol 90 mg/mL
Toxicity profile of small-molecule IAP antagonist GDC-0152 is linked to TNF-α pharmacology.
Erickson RI, et al. Toxicol Sci. 2013 Jan;131(1):247-58. PMID: 22956632.
Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152).
Flygare JA, et al. J Med Chem. 2012 May 10;55(9):4101-13. PMID: 22413863.
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