Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo

• Published in: Scientific Reports Vol. 10; no. 1; pp. 21671 - 16
• Main Authors: Sakamoto, Kotaro, Masutani, Teruaki, Hirokawa, Takatsugu
• Format: Journal Article
• Language: English
• Published: London Springer Science and Business Media LLC 10.12.2020; Nature Publishing Group UK; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/67; Amino Acid Sequence; Amino acids; Animals; Antineoplastic Agents; Cancer therapies; Cell Line, Tumor; Cell Proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Chemotherapy; Deoxycytidine; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug delivery; Drug development; Drug Therapy, Combination; Gemcitabine; Genes, ras; Genes, ras - genetics; H-Ras protein; Humanities and Social Sciences; Intravenous administration; K-Ras protein; Lung cancer; Lung Neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medicine; Mice; Molecular Targeted Therapy; multidisciplinary; Mutation; Neoplasm Transplantation; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Peptides; Peptides - administration & dosage; Peptides - chemistry; Peptides - pharmacology; Protein interaction; Q; R; Ras protein; Rats; Science; Science (multidisciplinary); Therapeutic targets; Xenografts
• DOI: 10.1038/s41598-020-78712-5
• ISSN: 2045-2322

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).