jm9b01979_si_002.pdf (547.72 kB)
Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase
journal contributionposted 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.
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