Targeting Ras with Macromolecules

Abstract

Activating Ras mutations are associated with ∼30% of all human cancers and the four Ras isoforms are highly attractive targets for anticancer drug discovery. However, Ras proteins are challenging targets for conventional drug discovery because they function through intracellular protein-protein interactions and their surfaces lack major pockets for small molecules to bind. Over the past few years, researchers have explored a variety of approaches and modalities, with the aim of specifically targeting oncogenic Ras mutants for anticancer treatment. This perspective will provide an overview of the efforts on developing "macromolecular" inhibitors against Ras proteins, including peptides, macrocycles, antibodies, nonimmunoglobulin proteins, and nucleic acids.

Figure 1.

Ras structure and function. (A) Interconversion between inactive Ras-guanosine diphosphate (GDP) and active Ras-guanosine triphosphate (GTP) mediated by guanine nucleotide exchange factor (GEF) and GTPase-activating protein (GAP). The active Ras-GTP interacts with effector proteins and activates downstream cell signaling. (B) Structure of K-Ras bound with GppNp, a nonhydrolyzable analog of GTP. The switch I/II regions are shown in red, the dimerization interface in blue, and the bound nucleotide analog is shown as sticks. (Figure was recreated from PDB data [pdb5p21].)

Figure 2.

Molecular modalities that have been used as direct Ras inhibitors. (A) Small molecules (example shown is the K-Ras^G12C-selective inhibitor by Ostrem et al. 2013); (B) stapled peptides (example shown is SAH-SOS1); (C) macrocyclic peptides (example shown is cyclorasin 9A5); (D) monoclonal antibodies; (E) intrabodies (the V_H and V_L regions of an antibody linked by a polypeptide or disulfide bond); (F) affibodies; and (G) monobodies (the tenth fibronectin type III domain of human fibronectin).

Figure 3.

Structures of macrocyclic peptidyl Ras inhibitors.