Fig. 1: Schematic overview of selected drugs targeting Ras lipidation and trafficking.
From: Drugging Ras trafficking—are there new roads to travel?
Example compounds that inhibit or modulate indicated targets are shown with their names. Several are approved or clinical-stage drugs (all compounds in the bottom row). The left-hand side depicts lipid modification pathways of Ras, while the right side shows the action of trafficking chaperones of Ras. On the endoplasmic reticulum, all Ras proteins are initially farnesylated on the C-terminal cysteine of the CAAX-box (C: cysteine, A: aliphatic residue, X: any residue) followed by subsequent RCE1-mediated AAX-tripeptide cleavage and carboxymethylation of the cysteine by ICMT (enzymes shown in turquoise). Subsequently, K-Ras4B becomes trapped on the recycling endosome (not shown), while the other Ras isoforms are trapped on the Golgi-apparatus by palmitoylation. Enzymes mediating re- and depalmitoylation are shown in gray hues. All Ras are subsequently vesicularly transported to the plasma membrane, where they laterally segregate into distinct nanoclusters. Phosphatidylserine (PS) has emerged as an important lipid to mediate this process by directly interacting with the most C-terminal residues of Ras proteins. Extraction or dissociation from the plasma membrane is enhanced after depalmitoylation. In addition, endocytosis may return Ras into the cycle for vesicular transport. Trafficking chaperones (purple hues) solubilize Ras whenever it has to move between membranes by binding to the farnesyl moiety thus allowing its long-range diffusion. This is necessary to fuel the transport cycle to the plasma membrane and other organelles. Given the distinct client spectrum and their potential involvement in specific cell- and developmental pathways, trafficking chaperones may offer more discrete drug targeting opportunities than broad inhibition of the lipidation machinery.
