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

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 a...

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Autores principales:	Kotaro Sakamoto, Teruaki Masutani, Takatsugu Hirokawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1169d92c6a314ea185bfdf3f8304635f
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spelling	oai:doaj.org-article:1169d92c6a314ea185bfdf3f8304635f2021-12-02T16:18:03ZGeneration of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo10.1038/s41598-020-78712-52045-2322https://doaj.org/article/1169d92c6a314ea185bfdf3f8304635f2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78712-5https://doaj.org/toc/2045-2322Abstract 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).Kotaro SakamotoTeruaki MasutaniTakatsugu HirokawaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kotaro Sakamoto Teruaki Masutani Takatsugu Hirokawa Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo
description	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).
format	article
author	Kotaro Sakamoto Teruaki Masutani Takatsugu Hirokawa
author_facet	Kotaro Sakamoto Teruaki Masutani Takatsugu Hirokawa
author_sort	Kotaro Sakamoto
title	Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo
title_short	Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo
title_full	Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo
title_fullStr	Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo
title_full_unstemmed	Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo
title_sort	generation of ks-58 as the first k-ras(g12d)-inhibitory peptide presenting anti-cancer activity in vivo
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/1169d92c6a314ea185bfdf3f8304635f
work_keys_str_mv	AT kotarosakamoto generationofks58asthefirstkrasg12dinhibitorypeptidepresentinganticanceractivityinvivo AT teruakimasutani generationofks58asthefirstkrasg12dinhibitorypeptidepresentinganticanceractivityinvivo AT takatsuguhirokawa generationofks58asthefirstkrasg12dinhibitorypeptidepresentinganticanceractivityinvivo
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Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo

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