期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 12, 页码 2757-2761出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.04.063
关键词
K-Ras(G12D); Cyclic peptide; Mutant selective; Cysteine bridging; Mono-methylene
资金
- Takeda Pharmaceutical Company, Ltd., Fujisawa, Japan
A structure-activity relationship study of a K-Ras(G12D) selective inhibitory cyclic peptide, KRpep-2d was performed. Alanine scanning of KRpep-2d focusing on the cyclic moiety showed that Leu(7), Ile(9), and Asp(12) are the key elements for K-Ras(G12D) selective inhibition of KRpep-2d. The cysteine bridging was also examined to identify the stable analog of KRpep-2d under reductive conditions. As a result, the KRpep-2d analog (12) including mono-methylene bridging showed potent K-Ras(G12D) selective inhibition in both the presence and the absence of dithiothreitol. This means that mono-methylene bridging is an effective strategy to obtain a reduction-resistance analog of parent disulfide cyclic peptides. Peptide 12 inhibited proliferation of K-Ras(G12D)-driven cancer cells significantly. These results gave valuable information for further optimization of KRpep-2d to provide novel anti-cancer drug candidates targeting the K-Ras(G12D) mutant. (C) 2017 Elsevier Ltd. All rights reserved.
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