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[3]. These include the ability to proliferate, evade apoptosis, reprogram cell metabolism, induce angiogenesis, activate invasion and metastasis, and escape immune destruction[4]. 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[5]. Downregulation of activated Ras reverses the transformed phenotype of cells and results in the dramatic regression of tumors in murine xenograft models[6]. K-Ras-IN-1（MDK-3017）is a K-Ras inhibitor that binds to K-Ras (wild type), K-Ras (G12D), K-Ras (G12V), and H-Ras and block binding to Sos which causes the inhibition of Sos-mediated nucleotide exchange. These molecules represent a starting point for obtaining probe molecules useful in elucidating new insights into Ras signaling and for discovering K-Ras inhibitors for the treatment of cancer[7].
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