title: An inhibitor of apoptosis protein antagonist T-3256336 potentiates the antitumor efficacy of the Nedd8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924).
abstract: Inhibitors of apoptosis proteins (IAPs) are antiapoptotic regulators that block cell death, and are frequently overexpressed in several human cancers, where they facilitate evasion of apoptosis and promote cell survival. IAP antagonists are also known as second mitochondria-derived activator of caspase (SMAC)-mimetics, and have recently been considered as novel therapeutic agents for inducing apoptosis, alone and in combination with other anticancer drugs. In this study, we showed that T-3256336, the orally available IAP antagonist has synergistically enhances the antiproliferative effects of the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and these effects were attenuated by a TNFα-neutralizing antibody. In the present mechanistic analyses, pevonedistat induced TNFα mRNA and triggered IAP antagonist-dependent extrinsic apoptotic cell death in cancer cell lines. Furthermore, synergistic effects of the combination of T-3256336 and pevonedistat were demonstrated in a HL-60 mouse xenograft model. Our findings provide mechanistic evidence of the effects of IAP antagonists in combination with NAE inhibitors, and demonstrate the potential of a new combination therapy for cancer.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan. Electronic address: hiroyuki.sumi@takeda.com.
authors: Hiroyuki
authors: H
authors: Sumi
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
authors: Masakazu
authors: M
authors: Inazuka
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
authors: Megumi
authors: M
authors: Morimoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
authors: Ryosuke
authors: R
authors: Hibino
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
authors: Kentaro
authors: K
authors: Hashimoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
authors: Tomoyasu
authors: T
authors: Ishikawa
authors: Discovery, Millennium Pharmaceuticals, Inc., Cambridge, MA, 02139, USA.
authors: Keisuke
authors: K
authors: Kuida
authors: Discovery, Millennium Pharmaceuticals, Inc., Cambridge, MA, 02139, USA.
authors: Peter G
authors: PG
authors: Smith
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
authors: Sei
authors: S
authors: Yoshida
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan. Electronic address: masato.yabuki@takeda.com.
authors: Masato
authors: M
authors: Yabuki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D000075687:NEDD8 Protein; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage*; D011719:Pyrazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D016896:Treatment Outcome; D014452:Ubiquitins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D051034:Inhibitor of Apoptosis Proteins; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D009842:Oligopeptides; D011719:Pyrazines; D011743:Pyrimidines; C000607552:T-3256336; D014452:Ubiquitins; C539933:pevonedistat
keywords: IAP antagonist; Nedd8-activating engyme inhibitor; Pevonedistat; T-3256336; TNFα