title: Antitumor activity and pharmacodynamic biomarkers of a novel and orally available small-molecule antagonist of inhibitor of apoptosis proteins.
abstract: 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.
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Japan. hiroyuki.sumi@takeda.com
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sumi
authors.forename: Masato
authors.initials: M
authors.lastname: Yabuki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Iwai
authors.forename: Megumi
authors.initials: M
authors.lastname: Morimoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Hibino
authors.forename: Masakazu
authors.initials: M
authors.lastname: Inazuka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kosugi
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Aoyama
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Mie
authors.initials: M
authors.lastname: Yoshimatsu
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Sei
authors.initials: S
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D011719:Pyrazines; C000607552:T-3256336; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D020169:Caspases