title: Current status of the development of Ras inhibitors.
abstract: Despite the importance of ras as driver genes in many cancers, clinically effective anti-cancer drugs targeting their products, Ras, have been unavailable so far, which was in part ascribable to the apparently 'undruggable' nature of their tertiary structures. Nonetheless, recent studies in academia and industry have identified novel surface pockets accepting small-molecule ligands in both their active GTP-bound and inactive GDP-bound forms (Ras•GTP and Ras•GDP, respectively), which has led to a surge of investigations into the discovery of Ras-specific inhibitors particularly by utilizing their structural information for structure-based drug design (SBDD). We have been developing Ras inhibitors by SBDD targeting a novel conformation of Ras•GTP called state 1, possessing 'druggable' surface pockets, which emerges from the conformational dynamics. In this article, we will survey Ras functions from the structural biological point of view and summarize the current status of the development of Ras inhibitors including our own.
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan sfumi@med.kobe-u.ac.jp.
authors.forename: Fumi
authors.initials: F
authors.lastname: Shima
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yoshikawa
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Isa
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan kataoka@people.kobe-u.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018631:ras Proteins
keywords: NMR; Ras; X-ray crystallography; anti-cancer drugs; drug design; structure-based