Flourishing innovation in KRAS targeting: Recent advances in medicinal chemistry strategies and future perspectives.

The Kirsten rat sarcoma viral oncogene homolog (KRAS), one of the most frequently mutated oncogenes in human cancers, has long been regarded as an "undruggable" target due to its smooth protein surface and high affinity for GTP. The landmark approval of Sotorasib in 2021, the first covalent KRAS inhibitor, shattered this dogma, ushering in a new era of targeted therapy for KRAS-mutant cancers, which also has catalyzed an explosion of innovative strategies extending far beyond covalent G12C targeting. This work highlight reviewed the diverse medicinal chemistry methodologies employed in the development of KRAS-targeted therapeutics. Key strategies discussed include the design of direct inhibitors for specific mutant subtypes (including KRAS, KRAS, and pan-RAS), indirect inhibitors strategy, molecular glue technology, PROTAC strategies, and combination dosing regimens. Additionally, it encompasses structure-activity relationship (SAR) investigations and activity optimization processes and pharmacokinetic properties studies of representative molecules. Furthermore, we critically evaluate existing challenges in developing small-molecule KRAS modulators while discussing emerging opportunities in overcoming on-target resistance, aiming to offer valuable insights and perspectives for future research in this rapidly evolving field.