Molecular approaches towards an anti-ras drug

Abstract

The ras proteins have intrinsic biochemical properties that are similar to those of the guanine nucleotide binding regulatory proteins (G-proteins). Increased oncogenic potential results from amino acid substitutions that, by altering either the intrinsic GTPase activity or the GDP/GTP exchange rate, would lead to an increase in the level of the ras-GTP complex. The functional similarity between the ras oncogene proteins and the G-proteins suggests several mechanisms for an anti-ras drug. Anti-ras drugs could act either by retarding the formation of the biologically active GTP complex of the protein or by preventing the ras protein from interacting with its yet-to-be-identified target. Mutagenesis studies of Harvey (Ha) ras have identified the residues involved in GDP and GTP binding, the residues that constitute the epitope for the neutralizing antibody Y13-259 (63-73) and a region (32-40) that is required for effector action. Computer modeling combined with immunological characterization has suggested some structural properties of this putative 'effector' region.