Journal of Medicinal Chemistry p. 3215 - 3226 (2020)
Update date:2022-08-15
Topics:
Tanaka, Yuta
Kurasawa, Osamu
Yokota, Akihiro
Klein, Michael G.
Ono, Koji
Saito, Bunnai
Matsumoto, Shigemitsu
Okaniwa, Masanori
Ambrus-Aikelin, Geza
Morishita, Daisuke
Kitazawa, Satoshi
Uchiyama, Noriko
Ogawa, Kazumasa
Kimura, Hiromichi
Imamura, Shinichi
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.
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