The Endeavours in RAS Inhibition - the Past, Present, and Future

KRAS mutations are known to be the most recurrent gain-of-function changes instigated in patients with cancer. The RAS gene family is often mutated in most of the human cancers, and the pursuit of inhibitors that bind to mutant RAS continues as a foremost target. RAS is a small GTPase that controls numerous cellular functions, including cell proliferation, growth, survival, and gene expression. RAS is hence closely engaged in cancer pathogenesis. The recent achievements in the discovery of RAS inhibitors imply that the inhibition of RAS oncogene may soon go into clinical trials. This review article describes the role of RAS in cancer drug discovery, the diverse methodologies used to develop direct or indirect RAS inhibitors, and emphasize the current accomplishments in the progress of novel RAS inhibitors. In short, this review focuses on the different attributes of RAS that have been targeted by a range of inhibitors consisting of membrane localization, the active form of RAS, downstream regulator binding, and nucleotide exchange binding. A detailed explanation of RAS and its involvement in cancer drug discovery together with historical aspects are mentioned first followed by a brief outline of the different approaches to target RAS.