Abstract
Ras mutations (e.g., occur in K-Ras, N-Ras, and H-Ras) are one of the most desirable and promising drug targets in chemotherapy treatments for cancer. However, there are still no approved drugs directly targeting mutated Ras. In 2017, an artificial cyclic peptide, KRpep-2d, was discovered as the first selective inhibitor of K-Ras(G12D), the most frequent K-Ras mutation. Here, we report the generation of KS-58, a KRpep-2d derivative that is identified as a bicyclic peptide and possess unnatural amino acid structures. Our in vitro data and molecular dynamics simulations suggest that KS-58 enters cells and blocks intracellular Ras–effector protein interactions. KS-58 selectively binds to K-Ras(G12D) and suppresses the in vitro proliferation of the human lung cancer cell line A427 and the human pancreatic cancer cell line PANC-1, both of which express K-Ras(G12D). Moreover, KS-58 exhibits anti-cancer activity when given as an intravenous injection to mice with subcutaneous or orthotropic PANC-1 cell xenografts. The anti-cancer activity is further improved by combination with gemcitabine. To the best of our knowledge, this is the first report of K-Ras(G12D)-selective inhibitory peptide presenting in vivo anti-cancer activity. KS-58 is an attractive lead molecule for the development of novel cancer drugs that target K-Ras(G12D).
Highlights
IntroductionGDP-bound Ras signals OFF states, while GTP-bound Ras signals ON states
These two Ras states are supported by guanine nucleotide exchange factors (GEFs), such as Son of Sevenless homolog 1 (SOS1) and GTPase-accelerating proteins (GAPs)
The GTP-bound Ras interacts with downstream signal molecules, such as B-Raf proto-oncogene serine/threonine kinase (BRAF) and phosphoinositide 3-kinase (PI3K)
Summary
GDP-bound Ras signals OFF states, while GTP-bound Ras signals ON states This molecular switch cycle controls the intracellular translation of extracellular signals through the activation of cell surface receptors (e.g., epidermal growth factor receptor or fibroblast growth factor receptors). These two Ras states are supported by guanine nucleotide exchange factors (GEFs), such as Son of Sevenless homolog 1 (SOS1) and GTPase-accelerating proteins (GAPs). GTP is hydrolyzed and released from Ras via intrinsic GTPase activity and GAPs. In cancer cells, single amino acid mutations at multiple positions of Ras, which contains 188–189 amino acid residues, are frequently observed.
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