discovery of selective atp-competitive eif4a3 inhibitors：（发现选择性atp-competitive eif4a3抑制剂）.pdfVIP

Bioorganic Medicinal Chemistry 25 (2017) 2200–2209 Contents lists available at ScienceDirect Bioorganic Medicinal Chemistry journal homepage: www.else /locate/bmc Discovery of selective ATP-competitive eIF4A3 inhibitors Masahiro Ito a,⇑, Misa Iwatani a, Yusuke Kamada a, Satoshi Sogabe a, Shoichi Nakao a, Toshio Tanaka a, Tomohiro Kawamoto a, Samuel Aparicio b, Atsushi Nakanishi a, Yasuhiro Imaeda a,⇑ a Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan b Department of Molecular Oncology, BC Cancer Agency, 675 W10th Avenue, Vancouver, BC V5Z 1L3, Canada a r t i c l e i n f o a b s t r a c t Article history: Eukaryotic initiation factor 4A3 (eIF4A3), an ATP-dependent RNA helicase, is a core component of exon Received 22 December 2016 junction complex (EJC). EJC has a variety of roles in RNA metabolism such as translation, surveillance, Revised 15 February 2017 and localization of spliced RNA. It is worthwhile to identify selective eIF4A3 inhibitors with a view to Accepted 16 February 2017 investigating the functions of eIF4A3 and EJC further to clarify the roles of the ATPase and helicase activ- Available online 20 February 2017 ities in cells. Our chemical optimization of hit compound 2 culminated in the discovery of ATP-compet- itive eIF4A3 inhibitor 18 with submicromolar ATPase inhibitory activity and