Annual review of KRAS inhibitors in 2022

Kirsten rat sarcoma viral (KRAS) oncogene is the most commonly mutated isoform of Ras, accounting for 85% of RAS-driven human cancers. KRAS functioning as a signaling hub participates in multiple cellular signaling pathways and regulates a variety of critical processes such as cell proliferation, differentiation, growth, metabolism and migration. Over the past decades, KRAS oncoprotein has been considered as an "undruggable" target due to its smooth surface and high GTP/GDP affinity. The breakthrough in directly targeting G12C mutated-KRAS and recently approved covalent KRAS^G12C inhibitors sotorasib and adagrasib broke the myth of KRAS undruggable and confirmed the directly targeting KRAS as one of the most promising strategies for the treatment of cancers. Targeting KRAS^G12C successfully enriched the understanding of KRAS and brought opportunities for the development of inhibitors to directly target Other KRAS mutations. With the stage now set for a new era in the treatment of KRAS-driven cancers, the development of KRAS inhibitors also enters a booming epoch. In this review, we overviewed the research progress of KRAS inhibitors with the potential to treat cancers covering articles published in 2022. The design strategies, discovery processes, structure-activity relationship (SAR) studies, cocrystal structure analysis as well as in vitro and in vivo activity were highlighted with the aim of providing updated sight to accelerate the further development of more potent inhibitors targeting various mutated-KRAS with favorable drug-like properties.

Irreversible inhibitors; KRAS; PROTACs; Peptides; Reversible inhibitors.