Discovery of selective ATP-competitive eIF4A3 inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 7; pp. 2200 - 2209
• Main Authors: Ito, Masahiro, Iwatani, Misa, Kamada, Yusuke, Sogabe, Satoshi, Nakao, Shoichi, Tanaka, Toshio, Kawamoto, Tomohiro, Aparicio, Samuel, Nakanishi, Atsushi, Imaeda, Yasuhiro
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2017; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; ATP-competitive type inhibitors; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; DEAD-box RNA Helicases - antagonists & inhibitors; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Eukaryotic initiation factor 4A3 (eIF4A3) inhibitors; Eukaryotic Initiation Factor-4A - antagonists & inhibitors; Exon junction complex (EJC); High-Throughput Screening Assays; History, Medieval; Isothermal titration calorimetry (ITC); Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Proton Magnetic Resonance Spectroscopy; RNA helicase; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Surface plasmon resonance (SPR); EDC; SAR; HOBtNH3; MeCN; CD3OD; Isothermal titration calorimetry (ITC); iPrOH; Exon junction complex (EJC); Pd(dppf)Cl2; FITC; SPR; Selectfluor; HOBt; CDCl3; Pd(PPh3)Cl2; EtOAc; EDC·HCl; DIPEA; POCl3; NaOMe; Eukaryotic initiation factor 4A3 (eIF4A3) inhibitors; Pd/C; BRR2; Surface plasmon resonance (SPR); MeOH; Poly(U); DMSO-d6; ITC; DHX29; eIF4A; RNA helicase; ATP-competitive type inhibitors; EJC; MESSENGER-RNA; BOX RNA HELICASE; NONSENSE-MEDIATED DECAY; EXON JUNCTION COMPLEX; FAMILY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.02.035

[Display omitted] Eukaryotic initiation factor 4A3 (eIF4A3), an ATP-dependent RNA helicase, is a core component of exon junction complex (EJC). EJC has a variety of roles in RNA metabolism such as translation, surveillance, and localization of spliced RNA. It is worthwhile to identify selective eIF4A3 inhibitors with a view to investigating the functions of eIF4A3 and EJC further to clarify the roles of the ATPase and helicase activities in cells. Our chemical optimization of hit compound 2 culminated in the discovery of ATP-competitive eIF4A3 inhibitor 18 with submicromolar ATPase inhibitory activity and excellent selectivity over other helicases. Hence, compound 18 could be a valuable chemical probe to elucidate the detailed functions of eIF4A3 and EJC.