Elena De Vita, Maria Maneiro, and Edward W. Tate
ACS Central Science Article ASAP
More than four decades since their first identification, small monomeric guanosine triphosphatases (GTPases) remain among the most studied oncogenic proteins. Three GTPases in the rat sarcoma viral oncogene (RAS) family, KRAS, NRAS, and HRAS, are activated by “gain-of-function” mutations in up to 25% of all cancers, driving proliferative signaling to support tumor growth.(1) Their flat topology and lack of a clear ligand binding site (with the exception of the undruggable GTP pocket) has given rise to a wide range of indirect strategies to target RAS proteins with varying degrees of success (Figure 1A).(1) Mutant KRAS remains among the hottest targets in oncology, and concerted efforts to target oncogenic KRAS culminated in 2019–2020 with the discovery of allosteric covalent inhibitors that attack the nucleophilic cysteine residue, which is present uniquely in this specific KRAS mutant. The work of numerous academic and industry teams ultimately delivered four KRAS covalent inhibitors currently in clinical trials for cancer.(2) Among these, Mirati Therapeutics’ drug candidate (Figure 1A) has shown promising results and tolerability in patients affected by nonsmall cell lung cancer (NSCLC) and colorectal cancer (CRC) driven by KRAS mutant.(3) Nevertheless, the search for improved strategies continues, and in the current issue, the Crews laboratory has used as a warhead in the first cell-active PROteolysis TArgeting Chimera (PROTAC) against KRAS.(4) This work elegantly illustrates the differentiating opportunities and rational design challenges of covalent PROTACs, and delivers striking insights into the trade-offs of inhibition versus degradation.