A guanine derivative as a new MEK inhibitor produced by Streptomyces sp. MK63-43F2

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...

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Bibliographic Details
Published in:Journal of antibiotics 2018-01, Vol.71 (1), p.135-138
Main Authors: Iijima, Masatomi, Kubota, Yuji, Sawa, Ryuichi, Kubota, Yumiko, Hatano, Masaki, Igarashi, Masayuki, Kawada, Manabu, Momose, Isao, Takekawa, Mutsuhiro, Shibasaki, Masakatsu
Format: Article
Language:English
Subjects:
631/92/349
692/308/153
96/95
Antibiotics
Antineoplastic drugs
Antitumor agents
Bacteriology
Biological activity
Biomedical and Life Sciences
Bioorganic Chemistry
Cancer
Carbon
Cell growth
Cell proliferation
Chemistry
Colorectal carcinoma
Ethanol
Extracellular signal-regulated kinase
Guanine
Kinases
Lead compounds
Life Sciences
MAP kinase
Medicinal Chemistry
MEK inhibitors
MEK1 kinase
Melanoma
Metabolic pathways
Metabolites
Microbiology
Mutation
Organic Chemistry
Phosphorylation
Protein kinase
Proteins
Raf protein
Streptomyces
Thyroid
Thyroid carcinoma
Thyroid gland
Tumors
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Summary: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.
ISSN:0021-8820
1881-1469
DOI:10.1038/ja.2017.100