Niida Ayumu, Sasaki Shigekazu, Yonemori Kazuko, Sameshima Tomoya, Yaguchi Masahiro, Asami Taiji, Sakamoto Kotaro, Kamaura Masahiro
Research, Takeda Pharmaceutical Company, Ltd., 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
Research, Takeda Pharmaceutical Company, Ltd., 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem Lett. 2017 Jun 15;27(12):2757-2761. doi: 10.1016/j.bmcl.2017.04.063. Epub 2017 Apr 21.
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, Ile, and Asp 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.
对一种K-Ras（G12D）选择性抑制环肽KRpep-2d进行了构效关系研究。聚焦于环部分对KRpep-2d进行丙氨酸扫描表明，亮氨酸、异亮氨酸和天冬氨酸是KRpep-2d对K-Ras（G12D）选择性抑制的关键元素。还研究了半胱氨酸桥连，以确定在还原条件下KRpep-2d的稳定类似物。结果，包括单亚甲基桥连的KRpep-2d类似物（12）在存在和不存在二硫苏糖醇的情况下均表现出对K-Ras（G12D）的有效选择性抑制。这意味着单亚甲基桥连是获得母体二硫键环肽的抗还原类似物的有效策略。肽12显著抑制了K-Ras（G12D）驱动的癌细胞的增殖。这些结果为进一步优化KRpep-2d以提供靶向K-Ras（G12D）突变体的新型抗癌药物候选物提供了有价值的信息。
