Abstract
Inhibitor of Apoptosis Proteins (IAPs) are cellular proteins that prevent cell death by apoptosis and are frequently overexpressed in cancer cells resulting in elevated levels leading to cancer survival and progression. Currently we are developing a class of compounds called SMAC mimetics that reverse the effects of IAPs including XIAP, cIAP‐1 and cIAP‐2 and ML‐IAP causing cancer cells to undergo apoptosis in a broad range of tumor types. TL32711 is a SMAC mimetic which has demonstrated potent and selective activity in several human tumor cell lines as well as in vitro inhibition of IAP target proteins. To determine translational effects in vivo, we evaluated PK/PD and single agent antitumor activity of TL32711 in an orthotopic human breast tumor xenograft model. Single agent toxicity as well as tumor growth inhibition, delay and regression were monitored in the study. The designated endpoint for the efficacy experiment was a mean control tumor volume of approximately 1 cm3.
TL32711 administered by intravenous injection on a q3dx5 schedule was well tolerated up to 10 mg/kg alone, the highest dose tested. The minimal effective dose was determined to be 1.25 mg/kg. When tumors were allowed to grow to 260 mm3 prior to initiation of treatment, the treatment effect was not diminished. PK/PD analysis of TL32711 found a longer half‐life of TL32711 in tumor compared to normal tissue and a time and dose dependent inhibition of the target protein cIAP‐1. The effects on the cIAP‐1 target were in good agreement with the tissues levels measured using a LC/MS method. TL32711 was not found to cross the blood brain barrier in this analysis.
Results from these studies confirm translational effects of TL32711 in a preclinical model of human breast cancer. In addition, PK/PD analysis demonstrated dose and time dependent target inhibition in vivo and decreased half life in tumor tissue.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B163.
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