Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Autor: Kage M; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Hayashi R; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan. Electronic address: hayashi.ryuji13@chugai-pharm.co.jp., Matsuo A; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Tamiya M; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Kuramoto S; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Ohara K; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Irie M; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Chiyoda A; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Takano K; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Ito T; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Kotake T; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Takeyama R; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Ishikawa S; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Nomura K; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Furuichi N; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Morita Y; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Hashimoto S; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Kawada H; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Nishimura Y; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Nii K; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Sase H; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Ohta A; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Kojima T; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Iikura H; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan., Tanada M; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan. Electronic address: tanadamkm@chugai-pharm.co.jp., Shiraishi T; Research Division, Chugai Pharmaceutical Co. Ltd., 216, Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-8602, Japan. Electronic address: shiraishitky@chugai-pharm.co.jp.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Aug 01; Vol. 110, pp. 117830. Date of Electronic Publication: 2024 Jul 06.
DOI: 10.1016/j.bmc.2024.117830
Abstrakt: Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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