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.
|Related IAP Products|
SM-164 is a potent cell-permeable and bivalent Smac mimetic which bind to a XIAP protein with a Ki value of 0.56 nM, and binds to cIAP-1 and cIAP-2 proteins with Ki values of 0.31 and 1.1 nM, respectively.
LCL161 is an orally bioavailable SMAC mimetic, potently binds to and inhibits multiple IAPs (i.e. XIAP, c-IAP).
BV6 is a small-molecule Smac mimetic, which antagonizes IAP proteins.
Birinapant (formerly TL32711) is a Smac mimetic acts as antagonist to cIAP1 and cIAP2.
AT-406 is an orally bioavailable potent IAP (inhibitor of apoptosis protein) of XIAP, cIAP1 and cIAP2 with Ki of 66.4 nM, 1.9 nM and 5.1 nM, respectively.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2017 AbMole BioScience. All Rights Reserved.