1. Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase
- Author
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Masanori Okaniwa, Geza Ambrus-Aikelin, Shigemitsu Matsumoto, Yuta Tanaka, Akihiro Yokota, Koji Ono, Kazumasa Ogawa, Daisuke Morishita, Satoshi Kitazawa, Osamu Kurasawa, Michael G. Klein, Shinichi Imamura, Hiromichi Kimura, Noriko Uchiyama, and Bunnai Saito
- Subjects
Conformational change ,Guanine ,Indoles ,Protein Conformation ,Spermidine ,Allosteric regulation ,DHPS ,Thiophenes ,Crystallography, X-Ray ,Structure-Activity Relationship ,chemistry.chemical_compound ,parasitic diseases ,Drug Discovery ,Humans ,Deoxyhypusine synthase ,Enzyme Inhibitors ,Enzyme Assays ,Hypusine ,Oxidoreductases Acting on CH-NH Group Donors ,Molecular Structure ,biology ,NAD ,High-Throughput Screening Assays ,Biochemistry ,chemistry ,biology.protein ,Molecular Medicine ,NAD+ kinase ,EIF5A ,Allosteric Site ,Protein Binding - Abstract
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.
- Published
- 2020
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