Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants

The RAS family of oncogenes ( KRAS , HRAS , NRAS ) is among the most frequently mutated genes in human cancer. Therapeutic development has largely focused on inhibitors for KRAS codon 12 mutations, while mutant-selective inhibitors for Q61 variants remain elusive. A common mechanistic feature of G12 and Q61 mutants is the reduced efficiency of GTP hydrolysis, which enriches RAS in its active, signaling-competent state. Here we report small molecules that accelerate GTP hydrolysis in KRAS-Q61 mutants as an alternative therapeutic strategy. These compounds compensate for the loss of the catalytic residue Gln61 by introducing a general base into the active site, selectively enhancing hydrolysis of KRAS-Q61X (X = H, L, K, R) mutants by up to 20-fold. In mutant cancer cell lines, these compounds reduce GTP-bound RAS levels and suppress downstream signaling. This work establishes a mechanistic foundation for small-molecule ‘GTPase activators’ and offers a new paradigm for targeting RAS-driven cancers.