Open AccessCurrent status of the development of Ras inhibitors
Author(s) -
Fumi Shima,
Shigeyuki Matsumoto,
Yoko Yoshikawa,
Takashi Kawamura,
Masayuki Isa,
Tohru Kataoka
Publication year - 2015
Publication title -
journal of biochemistry/the journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1756-2651
pISSN - 0021-924X
DOI - 10.1093/jb/mvv060
Subject(s) - druggability , gtp' , small molecule , gtpase , computational biology , drug discovery , small gtpase , chemistry , biology , cancer research , biochemistry , gene , enzyme , signal transduction
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.