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|
|Solubility (25°C)||DMSO 79 mg/mL
Ethanol 60 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.
|Related IAP Products|
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LBW242, a 3-mer and Smac mimetic, is a potent and orally active proapoptotic IAP inhibitor. LBW242 shows effects on mutant FLT3-expressing cells. LBW242 has activity against multiple myeloma, and potentiates TRAIL- and anticancer agent-mediated cell death of ovarian cancer cells.
UC-112 is a novel potent IAP(Inhibitor of apoptosis) inhibitor. UC-112 potently inhibit cell growth in two human melanoma (A375 and M14) and two human prostate (PC-3 and DU145) cancer cell lines(IC50=0.7-3.4 uM).
SBP-0636457 (SB1-0636457) is a SMAC mimetic, and as an IAP antagonist. SBP-0636457 binds to the BIR-domains of the IAP proteins, with a Ki of 0.27 μM. SBP-0636457 can be used for the research of solid tumors and hematologic cancers.
XIAP/cIAP1 antagonist-1 is a potent and orally active XIAP/cIAP1 antagonist with EC50s of 5.1 nM and 0.32 nM for XIAP and cIAP1, respectively. XIAP/cIAP1 antagonist-1 inhibits the tumor growth in dose-dependent manner in vivo.
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