RAS degraders: The new frontier for RAS-driven cancers

The function and significance of RAS proteins in cancer have been widely studied for decades. In 2013, the National Cancer Institute established the RAS Initiative to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes and to create effective therapies for RAS-driven cancers. This initiative spurred researchers to develop novel approaches and to discover small molecules targeting this protein that was at one time termed “undruggable.” More recently, advanced efforts in RAS degraders including PROTACs, linker-based degraders, and direct proteolysis degraders have been explored as novel strategies to target RAS for cancer treatment. These RAS degraders present new opportunities for RAS therapies and may prove fruitful in understanding basic cell biology. Novel delivery strategies will further enhance the efficacy of these therapeutics. In this review, we summarize recent efforts to develop RAS degraders, including PROTACs and E3 adaptor and ligase fusions as cancer therapies. This review also details the direct RAS protease degrader, RAS/RAP1-specific endopeptidase that directly and specifically cleaves RAS.