"目录号: HY-13638
Apoptosis-
GDC-0152 是一种有效的IAPs抑制剂，能够分别与XIAPBIR3 结合域，ML-IAP的 BIR 结合域，cIAP1和cIAP2的 BIR3 结合域结合，Ki值分别为 28，14，17 和 43 nM。
IAP
相关产品
LCL161-Birinapant-BV6-CUDC-427-AZD5582-Embelin-SM-164-AT-406-MX69-UC-112-
生物活性
Description
GDC-0152 is a potent inhibitor ofIAPswhich binds to theXIAPBIR3 domain, the BIR domain ofML-IAP, and the BIR3 domains ofcIAP1andcIAP2withKivalues of 28, 14, 17, and 43 nM, respectively.
IC50& Target
Ki: 28 nM (XIAP BIR3), 14 nM (MLIAP-BIR3), 17 nM (cIAP1-BIR3), 43 nM (cIAP2-BIR3)
In Vitro
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. In melanoma SK-MEL28 cells, the endogenous association of ML-IAP and Smac is also effectively abolished by GDC-0152. GDC-0152 leads 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[1].
In Vivo
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 ranging from 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].
Clinical Trial
NCT00977067
Genentech, Inc.
Solid Cancers
June 2007
Phase 1
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References
[1].Flygare JA, et al. Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). J Med Chem. 2012 May 10;55(9):4101-13.