K-Ras G12D inhibitor KS-58

Биологическая активность

K-Ras G12D ингибитор KS-58 is the first K-Ras(G12D) селективный, bicyclic peptide ингибитор with связывание Ki of 22 nM; KS-58 suppressed growth of A427 cells and PANC-1 cells (human pancreas carcinoma, G12D mutant) down to 21.1% and 50.1% at 30 uM. KS-58 showed significantly weaker клетка growth suppression activities against A549 (human lung carcinoma, G12S mutant), H1975 (human lung carcinoma, WT), MIA PaCa-2 (human pancreas carcinoma, G12C mutant), and Capan-1 (human pancreas carcinoma, G12V mutant) cells. KS-58 reduced the phosphorylation of ERK down to 26.0% and 57.6% at 30 uM, respectively. Biotin-KS-58 exhibited stronger связывание to K-Ras(G12D) than to other Ras proteins; KS-58 enters cells, binds to both forms of intracellular K-Ras(G12D)GDP/GTP, and inhibits K-Ras(G12D)GDP/GTP-effector protein interactions, thus preventing downstream Ras signal pathways, such as ERK, and suppressing клетка proliferation. KS-58 exhibits anti-cancer activity when given as an intravenous injection to mice with subcutaneous or orthotropic PANC-1 клетка xenografts.