American Chemical Society
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Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase

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journal contribution
posted on 2020-03-16, 04:31 authored by Yuta Tanaka, Osamu Kurasawa, Akihiro Yokota, Michael G. Klein, Koji Ono, Bunnai Saito, Shigemitsu Matsumoto, Masanori Okaniwa, Geza Ambrus-Aikelin, Daisuke Morishita, Satoshi Kitazawa, Noriko Uchiyama, Kazumasa Ogawa, Hiromichi Kimura, Shinichi Imamura
Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound (2) led to bromobenzothiophene (11g) with potent inhibitory activity against DHPS. X-ray crystallographic analysis of 11g complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.