KRpep-2d is a potent K-Ras inhibitor, discovered after optimization of an initial hit obtained by phage display technology. KRpep-2d inhibits the enzyme activity of K-Ras(G12D) with an IC50 of 1.6 nM, and with selectivity against wild-type (WT) K-Ras and the K-Ras(G12C) mutant in both cell-free enzyme and cell based assays. Mutated Ras proteins play important roles in cell differentiation, proliferation, and survival of various cancers, and K-Ras(G12D) is considered a very important target as K-Ras mutations underlie 86% of Ras-linked cancers, with 83% of K-Ras mutations being at the G12 residue. KRpep-2d can suppress ERK phosphorylation downstream of K-Ras(G12D) and reduce proliferation in A427 cancer cells.
