2. Academic Validation
  3. Discovery of selective ATP-competitive eIF4A3 inhibitors

Discovery of selective ATP-competitive eIF4A3 inhibitors

  • Bioorg Med Chem. 2017 Apr 1;25(7):2200-2209. doi: 10.1016/j.bmc.2017.02.035.
Masahiro Ito 1,  Misa Iwatani 2,  Yusuke Kamada 2,  Satoshi Sogabe 2,  Shoichi Nakao 2,  Toshio Tanaka 2,  Tomohiro Kawamoto 2,  Samuel Aparicio 3,  Atsushi Nakanishi 2,  Yasuhiro Imaeda 4
Affiliations

Affiliations

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: masahiro.ito@takeda.com.
  • 2 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 3 Department of Molecular Oncology, BC Cancer Agency, 675 W10th Avenue, Vancouver, BC V5Z 1L3, Canada.
  • 4 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yasuhiro.imaeda@takeda.com.
PMID: 28283335 DOI: 10.1016/j.bmc.2017.02.035
Abstract

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.

Keywords

ATP-competitive type inhibitors; Eukaryotic initiation factor 4A3 (eIF4A3) inhibitors; Exon junction complex (EJC); Isothermal titration calorimetry (ITC); RNA helicase; Surface plasmon resonance (SPR).

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