Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics

KRAS, the most frequently mutated oncogene, plays a predominant role in driving initiation and progression of cancers. Decades of effort to target KRAS using small molecules has been unsuccessful, causing KRAS to be considered an “undruggable” cancer target. However, this view began to change recently, as drug discovery techniques have developed several KRAS G12C allosteric inhibitors that are currently being evaluated in clinical trials. Herein we provide an in-depth analysis of the structure and binding pockets of KRAS, medicinal chemistry optimization processes, and the biological characterization of small-molecule inhibitors that directly target KRAS, including covalent allosteric inhibitors specific for the G12C mutant, GTP-competitive inhibitors targeting the nucleotide-binding site, and protein–protein interaction inhibitors that bind in the switch I/II pocket or the A59 site. Additionally, we propose potential challenges faced by these new classes of KRAS inhibitors under clinical evaluation.