2013年
Discovery of Small-Molecule Ras Inhibitors that Display Antitumor Activity by Interfering with Ras·GTP-Effector Interaction
Enzymes
- ,
- ,
- ,
- 巻
- 34
- 号
- 開始ページ
- 1
- 終了ページ
- 23
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/B978-0-12-420146-0.00001-9
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-RasP40D·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-RasT35S·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. © 2013 Elsevier Inc.
- リンク情報
- ID情報
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- DOI : 10.1016/B978-0-12-420146-0.00001-9
- ISSN : 1874-6047
- PubMed ID : 25034098
- SCOPUS ID : 84887226660