Discovery of Selective ATP-competitive eIF4A3 Inhibitors

Publication date: Available online 20 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Masahiro Ito, Misa Iwatani, Yusuke Kamada, Satoshi Sogabe, Shoichi Nakao, Toshio Tanaka, Tomohiro Kawamoto, Samuel Aparicio, Atsushi Nakanishi, Yasuhiro Imaeda
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 function of eIF4A3 and EJC.

Graphical abstract

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