American Association for Cancer Research
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Supplementary Figure S4 from Antitumor Activity and Pharmacodynamic Biomarkers of a Novel and Orally Available Small-Molecule Antagonist of Inhibitor of Apoptosis Proteins

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journal contribution
posted on 2023-04-03, 13:51 authored by Hiroyuki Sumi, Masato Yabuki, Kenichi Iwai, Megumi Morimoto, Ryosuke Hibino, Masakazu Inazuka, Kentaro Hashimoto, Yohei Kosugi, Kazunobu Aoyama, Shunsuke Yamamoto, Mie Yoshimatsu, Hideki Yamasaki, Ryuichi Tozawa, Tomoyasu Ishikawa, Sei Yoshida

PDF file - 57KB, Growth inhibition potency of T-3256336 on several cell lines



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 octahydro-pyrrolo[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-α–dependent extrinsic apoptosis signaling in cultured cells. In a MDA-MB-231-Luc breast cancer xenograft model, T-3256336 induced cIAP-1 degradation, TNF-α production, and caspase activation in tumors, which resulted in strong antitumor activities. T-3256336 induced increases in the plasma levels of TNF-α 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. ©2012 AACR.