An overview of PROTACs targeting KRAS and SOS1 as antitumor agents

KRAS is the most frequently mutated oncogene and its mutational activation drives approximately 25 % of human cancers. Son of Sevenless 1 (SOS1) plays a pivotal role in the KRAS signaling pathway through catalyzing the conversion of inactive GDP-bound KRAS to active GTP-bound KRAS, and is thus considered as a promising target for pan-KRAS inhibition. Currently, four KRAS^G12C-specific inhibitors, namely sotorasib, adagrasib, fulzerasib and garsorasib, have garnered regulatory approval. However, acquired resistance to KRAS^G12C inhibition rapidly emerges. In addition, the other prevalent KRAS mutations, including G12D and G12V, are still lacking effective therapeutic drugs. PROTAC-mediated KRAS and SOS1 degradation has been emerged as a promising strategy to overcome these issues, and achieved rapid progress in the recent years. This article provides an overview of the chemical structures, design strategies, structure-activity relationship (SAR) studies as well as in vitro and in vivo activities of the PROTACs degrading KRAS and SOS1, and sheds light on future challenges and opportunities to accelerate the development of new chemotherapies for KRAS-driven cancers.