Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile

Abstract

KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the εand η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer.

Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion

“…Arginine is a common residue in the active pocket of enzymes that use nucleotide molecules as substrates, such as AARSs and glycosyltransferases. Currently, there are few strategies to develop covalent inhibitors targeting arginine 37 . Covalent modifications with lower activity tend to have higher selectivity.…”

A covalent opsonization approach to enhance synthetic immunity against viral escape variants

“…Indeed, tuning covalent drug electrophile reactivity has been used successfully as a strategy to overcome KRAS G12C mutants in oncology. 29 Finally, our CVO strategy may be associated with an intrinsic resiliency to mutating viral RBD variants compared with engineered antibody therapeutics. This advantage is by virtue of leveraging amino acid tunable covalent affinity labeling chemistry as an alternative to highly specific biologic binding.…”

Drugging KRAS: current perspectives and state-of-art review

“…For the near future, the challenge is to better understand resistance mechanisms to G12C inhibitors, develop strategies to overcome on- and off-target resistance, and effectively target other commonly seen KRAS mutations. A noteworthy recent breakthrough is the chemical development of selective covalent ligands for the mutant arginine residue in KRAS G12R and mutant serine residue in KRAS G12S [ 168 , 169 ]. Combination therapies of KRAS inhibitors with other inhibitors, cytotoxic chemotherapy agents and immunotherapies are generating excitement, but we suggest cautious optimism and phase III evidence to define the effectiveness of these agents and their combinations.…”