Antitumor Activity and Pharmacodynamic Biomarkers of a Novel and Orally Available Small-Molecule Antagonist of Inhibitor of Apoptosis Proteins

作者：Sumi Hiroyuki^*; Yabuki Masato; Iwai Kenichi; Morimoto Megumi; Hibino Ryosuke; Inazuka Masakazu; Hashimoto Kentaro; Kosugi Yohei; Aoyama Kazunobu; Yamamoto Shunsuke; Yoshimatsu Mie; Yamasaki Hideki; Tozawa Ryuichi; Ishikawa Tomoyasu; Yoshida Sei

来源：Molecular Cancer Therapeutics, 2013, 12(2): 230-240.

DOI：10.1158/1535-7163.MCT-12-0699

Inhibitor of apoptosis proteins (IAP), which are key regulators of apoptosis, are inhibited by second mitochondria-derived activator of caspase (SMAC). Small-molecule IAP antagonists have recently been reported as novel therapeutic treatments for cancer. In this study, we showed that the octahydropyrrolo[1,2-a]pyrazine derivative, T-3256336, is a novel and orally available small-molecule IAP antagonist. T-3256336 selectively binds to and antagonizes protein interactions involving cellular IAP-1 (cIAP-1), cIAP-2, and X-linked IAP (XIAP). T-3256336 induced the rapid proteasomal degradation of cIAP-1 and activated TNF-alpha-dependent extrinsic apoptosis signaling in cultured cells. In a MDA-MB-231-Luc breast cancer xenograft model, T-3256336 induced cIAP-1 degradation, TNF-alpha production, and caspase activation in tumors, which resulted in strong antitumor activities. T-3256336 induced increases in the plasma levels of TNF-alpha and fragmented cytokeratin-18, which correlated with the antitumor potency in MDA-MB-231-Luc xenograft models. This study provided further insights into biomarkers of IAP antagonists. Furthermore, our data provided evidence that T-3256336 is a promising new anticancer drug worthy of further evaluation and development. Mol Cancer Ther; 12(2); 230-40.

• 出版日期2013-2