RSC-1255 (KRAS inhibitor 249C, V-ATPase inhibitor) is a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancer cells (A549 (KRASG12S), IC50=73 nM), binds to V-ATPase (Kd=23 nM) and inhibits its activity.
249C (RSC-1255) shows inhibition of viability in both Ras- and Raf-mutant cells with IC50 of 73 nM, 60 nM and 22 nM for A549 (KRASG12S), LOX IMVI (BRAFV600E), and MelJuso (HRASG13D and NRASQ61L), respectively.
249C (RSC-1255) blocks lysosomal acidification and autophagy progression. blocked ATP hydrolysis of intact mammalian V-ATPase purified from pig kidneys (but not yeast).
249C (RSC-1255) differentially inhibits fibroblasts bearing mutations in KRAS and BRAF via inhibition of lysosomal pH, V-ATPase activity, and macropinocytosis.
249C (RSC-1255) preferentially kills mouse embryonic fibroblasts bearing specific KRAS mutations with IC50 values: KRAS WT (1.25 µM); G13D (0.07 µM); G12V (0.15 µM); G12S (0.23 µM); G12D (0.3 µM); Q61L (0.31 µM); G12C (0.44 µM); Q61R (0.55 µM); and for BRAFV600E (0.11 µM).
249C (RSC-1255) inhibits macropinocytosis in a KRAS-mutant-dependent manner in MEFs expressing KRAS/BRAF mutants (KRASG13D, KRASG12V, and BRAFV600E), but less so in MEFs expressing KRAS WT.
249C (RSC-1255) treatment (10 mg/kg, twice a day, i.p.) inhibits in vivo growth of mutant KRAS (KRASG12S) in mouse xenograft models and shows pharmacodynamic safety.