The RAS oncogenes (KRAS, HRAS, NRAS) are among the most frequently mutated genes 9 in human cancer, affecting over three million patients annually. Therapeutic development has 10 largely focused on inhibitors for KRAS codon 12 mutations (G12C/D/V/S/R) which are key drivers 11 in lung, colorectal, and pancreatic cancers. In contrast, mutant-selective inhibitors for Q61 variants 12 remain elusive. A common mechanistic feature of G12 and Q61 mutants is the impaired hydrolysis 13 of GTP, which traps Ras in its active, signaling-competent state. We envisioned that an alternative 14 therapeutic strategy - reactivation of GTP hydrolysis - could address this shared oncogenic 15 mechanism. Here we report small moleculesthat accelerate GTP hydrolysis in K-Ras Q61 mutants. 16 These compounds compensate for the loss of the catalytic residue Gln61 by introducing a general 17 base into the active site, selectively enhancing hydrolysis of K-Ras Q61X (X = H, L, K, R) mutants 18 by up to 20-fold while sparing the wild-type protein. In mutant cancer cell lines, these compounds 19 reduce GTP-bound Ras levels and suppress downstream signaling. We show that the chemical 20 design principles are generalizable to other Ras isoforms. This work establishes a mechanistic 21 foundation for small-molecule “GTPase activators” and offers a new paradigm for targeting Ras22 driven cancers.