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Download fileDiscovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase
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 ImamuraDeoxyhypusine
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.
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tumor cell proliferationamide compoundNovel Allosteric InhibitorsNADeIF 5A activationeukaryotic translation initiation factor 5ring structurestarget DHPSeIF 5A HypusineDeoxyhypusine Synthase Deoxyhypusine synthasenovel allosteric sitehigh-throughput screeninghypusine modification11 g complexednovel therapyprotein translation11 g