title: Discovery of Novel 1,4-Diacylpiperazines as Selective and Cell-Active eIF4A3 Inhibitors.
abstract: Eukaryotic initiation factor 4A3 (eIF4A3), a member of the DEAD-box RNA helicase family, is one of the core components of the exon junction complex (EJC). The EJC is known to be involved in a variety of RNA metabolic processes typified by nonsense-mediated RNA decay (NMD). In order to identify molecular probes to investigate the functions and therapeutic relevance of eIF4A3, a search for selective eIF4A3 inhibitors was conducted. Through the chemical optimization of 1,4-diacylpiperazine derivatives identified via high-throughput screening (HTS), we discovered the first reported selective eIF4A3 inhibitor 53a exhibiting cellular NMD inhibitory activity. A surface plasmon resonance (SPR) biosensing assay ascertained the direct binding of 53a and its analog 52a to eIF4A3 and revealed that the binding occurs at a non-ATP binding site. Compounds 52a and 53a represent novel molecular probes for further study of eIF4A3, the EJC, and NMD.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masahiro
authors.identifier: 0000-0001-5965-535X
authors.initials: M
authors.lastname: Ito
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Douglas R
authors.identifier: 0000-0003-3940-6078
authors.initials: DR
authors.lastname: Cary
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Iwatani-Yoshihara
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yusuke
authors.identifier: 0000-0003-3701-2075
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency , 675 W. 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakanishi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Imaeda
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D010879:Piperazines; D039601:Eukaryotic Initiation Factor-4A; D000251:Adenosine Triphosphatases; C403493:EIF4A3 protein, human; D053487:DEAD-box RNA Helicases