Figure 1 from Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

RMC-6236 is a potent noncovalent inhibitor of the GTP-bound state of multiple RAS variants in vitro. A, Chemical structure of RMC-6236. B, Biochemical potency of RMC-6236 for wild-type KRAS, NRAS, HRAS, and several oncogenic RAS variants. EC₅₀ values shown for inhibition of RAS-RAF binding using recombinant proteins in vitro. Error bars indicate ± 95% CI. C, Immunoblot protein Western analyses of KRAS pathway targets in HPAC (KRASG12D/WT, PDAC) and Capan-2 (KRASG12V/WT, PDAC) cancer cells treated with RMC-6236 at the indicated concentrations and time points. D, RMC-6236 potency measured in the PRISM panel of cancer cell lines. Left, AUC difference between cell lines with and without a given gene mutation (x-axis) and the significance of the difference (y-axis). Points represent mutated genes. A negative AUC indicates increased sensitivity to RMC-6236 and positive AUC indicates resistance. Horizontal dashed line represents the P-value cutoff of 5 × 10⁻⁸. Vertical lines represent the absolute effect cutoff of 0.1. Right: AUC for KRAS mutant [glycine 12 depicted as KRASG12X (115 lines); all other KRAS mutations labeled KRASOther (42 lines)], NRAS mutant [glutamine 61 depicted as NRASQ61X (34 lines); all other NRAS mutations labeled as NRASOther (20 lines)], HRAS mutant, NF1 mutant, EGFR mutant, PTPN11 mutant, and BRAFV600E mutant cell lines are shown. Comparison of indicated groups was done by the Wilcoxon rank-sum test with continuity correction. (**, P < 0.01; ***, P < 0.001).