Prospective Development of Small Molecule Targets to Oncogenic Ras Proteins

Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.