Abstract
Selective inhibitors of K-Ras(G12S) mutations were developed that suppress oncogenic signaling.
Major Finding: Selective inhibitors of K-Ras(G12S) mutations were developed that suppress oncogenic signaling.
Concept: These inhibitors function through noncatalytic serine acylation using β-lactone as an electrophile.
Impact: The chemistry provided can be used for the selective targeting of other unactivated ligand-accessible serines.
Mutations in the small GTPase KRAS are some of the most frequent mutations observed in human cancers, making it an attractive therapeutic target. Covalent inhibitors of the oncogenic K-Ras(G12C) mutation have shown clinical success, but targeting other K-Ras mutations, which do not share the high nucleophilicity of the cysteine residue, continues to be an unsolved issue. One such difficult-to-target K-Ras mutation is the K-Ras(G12S) mutation, which accounts for 4.4% of all K-Ras mutations. Using methods to covalently target this serine residue, Zhang and colleagues present irreversible small-molecule inhibitors of K-Ras(G12S), indicating that β-lactone–possessing K-Ras ligands are potent electrophiles that can bind to the Switch-II pocket (S-IIP) of K-Ras and promote acylation of the mutant serine residue. Both the GTPase activity and oncogenic function of the K-Ras(G12S) mutation were confirmed, and, using lessons from both K-Ras(G12C) drug inhibition as well as β-lactone–containing natural products that inhibit catalytic threonine covalent bonding, inhibitors to target this mutant serine residue were synthesized. These inhibitors, which target the S-IIP allowing for privileged K-Ras drug binding, formed covalent adducts with GDP-bound K-Ras(G12S) but not with wild-type (WT) K-Ras, and reduced the guanine exchange factor–mediated GDP to GTP exchange. Moreover, serine acylation was observed with these inhibitors confirming their activity, and use of optimized versions in cancer cell lines revealed targeted inhibition and reduced levels of Ras-GTP, the active form of Ras, as well as downstream Ras effectors phospho-ERK and phospho-AKT in K-Ras(G12S)–mutant cell lines. These same inhibitor effects were not observed in cell lines with WT K-Ras or other K-Ras mutations like K-Ras(G12D). In summary, this work presents potential inhibitors for K-Ras(G12S) mutations that can be improved upon for eventual clinical use as well as provides a chemical strategy that can be used in the targeting of other ligand-accessible serine residues.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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