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.