sotorasib and ARS-1620

The protein KRAS has for decades been considered a holy grail of cancer drug discovery. For most of that time, it has also been considered undruggable. Since 2018, five compounds have entered the clinic targeting a single mutant form of KRAS, G12C. Here, we review each of these compounds along with additional approaches to targeting this and other mutants. Remaining challenges include expanding the identification of inhibitors to a broader range of known mutants and to conformations of the protein more likely to avoid development of resistance.

Topics: Acetonitriles; Animals; Antineoplastic Agents; Drug Design; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Mutant Proteins; Mutation; Piperazines; Precision Medicine; Protein Binding; Protein Conformation; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Quinazolines; Structure-Activity Relationship