一种由链霉菌属MK63-43F2产生的新型MEK抑制剂——鸟嘌呤衍生物。
A guanine derivative as a new MEK inhibitor produced by Streptomyces sp. MK63-43F2.
作者信息
Iijima Masatomi, Kubota Yuji, Sawa Ryuichi, Kubota Yumiko, Hatano Masaki, Igarashi Masayuki, Kawada Manabu, Momose Isao, Takekawa Mutsuhiro, Shibasaki Masakatsu
机构信息
Institute of Microbial Chemistry (BIKAKEN), Shizuoka, Japan.
Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
出版信息
J Antibiot (Tokyo). 2017 Sep 6. doi: 10.1038/ja.2017.100.
Mitogen-activated protein kinase (MAPK) pathways that direct cellular responses are involved in various biological processes; the RAS-RAF-MEK-ERK pathway is one of the most important MAPK pathways. It is frequently activated in human malignant tumors such as melanomas, thyroid tumors and colorectal carcinomas. Therefore, targeting this pathway has been considered an attractive strategy for new anticancer drugs. In particular, MEK is a promising target because it is a kinase that directly phosphorylates ERK. We performed a screening to discover new MEK inhibitors, and found a guanine derivative produced by Streptomyces sp. MK63-43F2. This guanine derivative was identified to be 2-amino-4-methoxy-5-cyanopyrrolo[2,3-d]pyrimidine (1) through spectroscopic analysis. Compound 1 inhibited MEK1 kinase activity in an ATP-dependent manner and suppressed the phosphorylation of ERK in cancer cells and cell proliferation. Therefore, 1 might be a potent lead compound for new MEK inhibitors.The Journal of Antibiotics advance online publication, 6 September 2017; doi:10.1038/ja.2017.100.
指导细胞反应的丝裂原活化蛋白激酶（MAPK）信号通路参与多种生物学过程；RAS-RAF-MEK-ERK信号通路是最重要的MAPK信号通路之一。它在人类恶性肿瘤如黑色素瘤、甲状腺肿瘤和结直肠癌中经常被激活。因此，靶向该信号通路被认为是新型抗癌药物的一个有吸引力的策略。特别是，MEK是一个有前景的靶点，因为它是一种直接磷酸化ERK的激酶。我们进行了一项筛选以发现新的MEK抑制剂，并发现了链霉菌属MK63-43F2产生的一种鸟嘌呤衍生物。通过光谱分析，该鸟嘌呤衍生物被鉴定为2-氨基-4-甲氧基-5-氰基吡咯并[2,3-d]嘧啶（1）。化合物1以ATP依赖的方式抑制MEK1激酶活性，并抑制癌细胞中ERK的磷酸化和细胞增殖。因此，1可能是新型MEK抑制剂的一种有效先导化合物。《抗生素杂志》在线优先发表，2017年9月6日；doi:10.1038/ja.2017.100。
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