GDC-0152 is a potent inhibitor of IAPs and 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 disrupts protein−protein interactions involving IAP proteins and pro-apoptotic molecules. In HEK293T cells transiently transfected, GDC-0152 disrupts XIAP binding to partially processed caspase-9 and the association of ML-IAP, cIAP1, and cIAP2 with Smac. In SK-MEL28 melanoma cells, GDC-0152 effectively abolishes the endogenous association of ML-IAP and Smac. It reduces cell viability in MDA-MB-231 breast cancer cells but not in normal human mammary epithelial cells (HMEC). GDC-0152 activates caspases 3 and 7 in a dose- and time-dependent manner. Additionally, GDC-0152 induces rapid degradation of cIAP1 in A2058 melanoma cells, with effective degradation observed at concentrations as low as 10 nM, consistent with its affinity for cIAP1 [1].
体内研究
GDC-0152 exhibits moderate predicted hepatic clearance based on metabolic stability assays conducted using human liver microsomes. Plasma−protein binding of GDC-0152 is moderate and consistent across species, including mice (88−91%), rats (89−91%), dogs (81−90%), monkeys (76−85%), and humans (75−83%) over the investigated concentration range (0.1−100 μM); rabbits show higher plasma−protein binding (95−96%). GDC-0152 does not preferentially distribute to red blood cells, with blood−plasma partition ratios ranging from 0.6 to 1.1 in all species tested. Pharmacokinetic parameters for GDC-0152 include a C max of 53.7 μM and AUC of 203.5 h·μM [1].
体外研究
GDC-0152 disrupts protein−protein interactions involving IAP proteins and pro-apoptotic molecules. In HEK293T cells transiently transfected, GDC-0152 disrupts XIAP binding to partially processed caspase-9 and the association of ML-IAP, cIAP1, and cIAP2 with Smac. In SK-MEL28 melanoma cells, GDC-0152 effectively abolishes the endogenous association of ML-IAP and Smac. It reduces cell viability in MDA-MB-231 breast cancer cells but not in normal human mammary epithelial cells (HMEC). GDC-0152 activates caspases 3 and 7 in a dose- and time-dependent manner. Additionally, GDC-0152 induces rapid degradation of cIAP1 in A2058 melanoma cells, with effective degradation observed at concentrations as low as 10 nM, consistent with its affinity for cIAP1 [1].
GDC-0152 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
A2058 cells
Function assay
15 mins
Induction of proteasomal degradation of cIAP1 in human A2058 cells after 15 mins by immunoblotting
22413863
HEK293T cells
1-50 μM
Function assay
2 h
Inhibition of Flag-tagged XIAP BIR3 domain binding to cIAP1 expressed in human HEK293T cells at 1 to 50 uM after 2 hrs by immunoprecipitation
22413863
MDA-MB-231 cells
Cytotoxicity assay
72 h
Cytotoxicity against human MDA-MB-231 cells assessed as decrease in cell viability after 72 hrs by CellTiter-Glo luminescent assay
22413863
SK-MEL28 cells
0.5 μM
Function assay
Inhibition of ML-IAP binding to Smax expressed in gemcitabine and zVAd treated human SK-MEL28 cells at 0.5 uM by immunoprecipitation
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