GDC-0152 是一种 IAP 抑制剂，可以与XIAP、cIAP1和cIAP2的 BIR3 结合域，以及ML-IAP的 BIR 结合域结合，Ki值分别为 28 nM、17 nM、43 nM 和 14 nM。

GDC-0152 is a potent inhibitor of IAPs.

GDC-0152 can block protein–protein interactions that involve IAP proteins and pro-apoptotic molecules. Using transiently transfected HEK293T cells, GDC-0152 is shown to disrupt XIAP binding to partially processed caspase-9 and to disrupt the association of ML-IAP, cIAP1, and cIAP2 with Smac. The endogenous association of ML-IAP and Smac is effectively also abolished by GDC-0152 in melanoma SK-MEL28 cells. GDC-0152 lead to a decrease in cell viability in the MDA-MB-231 breast cancer cell line, while having no effect on normal human mammary epithelial cells (HMEC). GDC-0152 is found to activate caspases 3 and 7 in a dose- and time-dependent manner. GDC-0152 is shown to induce rapid degradation of cIAP1 in A2058 melanoma cells. It effectively induces degradation of cIAP1 at concentrations as low as 10 nM, consistent with its affinity for cIAP1.

GDC-0152 has moderate predicted hepatic clearance based on metabolic stability assays conducted using human liver microsomes. Plasma–protein binding of GDC-0152 is moderate and comparable among mice (88–91%), rats (89–91%), dogs (81–90%), monkeys (76–85%), and humans (75–83%) over the range of concentrations investigated (0.1–100 μM); higher plasma–protein binding is observed in rabbits (95–96%). GDC-0152 does not preferentially distribute to red blood cells with blood–plasma partition ratios of 0.6 to 1.1 in all species tested. The pharmacokinetics for GDC-0152 is achieved with a C max of 53.7 μM and AUC of 203.5 h·μM. [1]

Fluorescence polarization-based competition assay: Inhibition constants ( Ki ) for the antagonists are determined by addition of the IAP protein constructs to wells containing serial dilutions of the antagonists or the peptide AVPW, and the Hid-FAM probe or AVP-diPhe-FAM probe, as appropriate, in the polarization buffer. Samples are read after a 30-minute incubation. Fluorescence polarization values are plotted as a function of the antagonist concentration, and the IC50 values are obtained by fitting the data to a 4-parameter equation using software. Ki values for the antagonists are determined from the IC50 valued.

MDA-MB-231 breast carcinoma cells and HMECs are treated with the indicated concentrations of GDC-0152. Cell death is assessed using the CellTiter-Glo luminescent cell viability assay 72 h following the start of treatment.(Only for Reference)

873652-48-3

C25H34N6O3S

498.65

GDC0152

DMSO:92 mg/mL (184.5 mM)
Ethanol:92 mg/mL (184.5 mM)
H2O:3 mg/mL (6.01 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years