Discovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation

Abstract

K-Ras is a small GTPase that functions as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states. The conversion of K-Ras-GDP to K-Ras-GTP is the rate-limiting step in the activation of K-Ras and is catalyzed by guanine nucleotide exchange factors such as the son of sevenless (Sos). Mutations in K-Ras fix the protein in the active state and endow cells with capabilities that represent the hallmarks of cancer.[1] These include the ability to proliferate, evade apoptosis, reprogram cell metabolism, induce angiogenesis, activate invasion and metastasis, and escape immune destruction.[2] Indeed, aberrant K-Ras signaling plays a role in 30% of all human cancers, with the highest incidence of activating mutations found in pancreatic (70-90%), colon (30-50%), and lung (20-30%) carcinomas.[3] Downregulation of activated Ras reverses the transformed phenotype of cells and results in the dramatic regression of tumors in murine xenograft models.[4] Thus, K-Ras inhibition represents an attractive therapeutic strategy for many cancers. However, Ras activation and signaling is accomplished primarily through protein-protein interactions. Such protein interfaces typically lack well-defined binding pockets and have been difficult to target with small molecules.[5]