title: Discovery of small-molecule Ras inhibitors that display antitumor activity by interfering with Ras·GTP-effector interaction.
abstract: Ras proteins, particularly their active GTP-bound forms (Ras·GTP), were thought "undruggable" owing to the absence of apparent drug-accepting pockets in their crystal structures. Only recently, such pockets have been found in the crystal structures representing a novel Ras·GTP conformation. We have conducted an in silico docking screen targeting a pocket in the crystal structure of M-Ras(P40D)·GTP and obtained Kobe0065, which, along with its analogue Kobe2602, inhibits binding of H-Ras·GTP to c-Raf-1. They inhibit the growth of H-rasG12V-transformed NIH3T3 cells, which are accompanied by downregulation of not only MEK/ERK but also Akt, RalA, and Sos, indicating the blockade of interaction with multiple effectors. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma carrying K-rasG12V. The nuclear magnetic resonance structure of a complex of the compound with H-Ras(T35S)·GTP confirms its insertion into the surface pocket. Thus, these compounds may serve as a novel scaffold for the development of Ras inhibitors with higher potency and specificity.
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
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, Kobe, 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, Kobe, 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, Kobe, Japan. Electronic address: kataoka@people.kobe-u.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054852:Small Molecule Libraries; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D006160:Guanosine Triphosphate; D018631:ras Proteins
keywords: Antitumor activity; Computer docking simulation; NMR; Ras inhibitor; Structure-based drug design; X-ray crystallography