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Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase.
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.
Afiliación
  • Tanaka Y; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Kurasawa O; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Yokota A; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Klein MG; Department of Structural Biology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
  • Ono K; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Saito B; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Matsumoto S; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Okaniwa M; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Ambrus-Aikelin G; Department of Structural Biology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.
  • Morishita D; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Kitazawa S; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Uchiyama N; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Ogawa K; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Kimura H; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Imamura S; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
J Med Chem ; 63(6): 3215-3226, 2020 03 26.
Article en En | MEDLINE | ID: mdl-32142284
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiofenos / Inhibidores Enzimáticos / Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH / Indoles Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiofenos / Inhibidores Enzimáticos / Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH / Indoles Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos