Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate eukaryotic initiation factor 4E (eIF4E) and play important roles in promoting tumorigenesis and metabolic disease. Thus, inhibiting these enzymes might be valuable in the treatment of such conditions. We designed and synthesized a series of 4-((4-fluoro-2-isopropoxyphenyl)amino)-5-methylthieno[2,3-d]pyrimidine derivatives, and evaluated their inhibitory activity against the MNKs. We found 15 compounds that were active as MNK inhibitors and that one in particular, designated MNK-7g, which was potent against MNK1 and substantially more potent against MNK2. The compound MNK-7g did not affect other signaling pathways tested and had no adverse effects on cell viability. As expected from earlier studies, MNK-7g also inhibited cell migration. Therefore, the compound MNK-7g, which forms an ionic bond with Asp226 in MNK2 and possesses a substituted aniline in a thieno[2,3-d] pyrimidine structure, is a promising starting point for the future development of novel drugs for treating or managing cancer and metabolic disease.
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PMID:Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold. 3049 89

MAP Kinase Interacting Serine/Threonine Kinase 1 (MNK1) play important roles in the signaling transduction of MAPK pathways. It is significantly overexpressed in renal clear cell carcinoma and head-neck squamous cell carcinoma tissues in both mRNA and protein levels. Based on the crystallographic structure of MNK1 protein and binding modes analysis of known MNK inhibitors, we have designed and synthesized a series of 4-aniline-thieno[2,3-d]pyrimidine derivatives as potential MNK1 inhibitors. These synthetic compounds are tested in biochemical and cell proliferation assays, and six of them display potent inhibitory capacity against MNK1 kinase and cancer cell lines. Compound 12dj with strongest inhibitory capacity is transferred to molecular mechanism studies, and the results indicated that 12dj remarkably suppresses the phosphorylation of EIF4E, a substrate of MNK1. And the expression levels of MNK1, ERK1/2 and pERK1/2 are not affected by compound 12dj incubation in SUNE-1 and 786-O cells. In summary, our works suggested that these novel 4-aniline-thieno[2,3-d]pyrimidine based MNK1 inhibitors might be attractive lead compounds for targeted therapy of renal cell carcinoma and nasopharyngeal carcinoma.
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PMID:Design, synthesis and biological evaluation of 4-aniline-thieno[2,3-d]pyrimidine derivatives as MNK1 inhibitors against renal cell carcinoma and nasopharyngeal carcinoma. 3101 65