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| Item Type: | Article |
|---|---|
| Title: | Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4 |
| Creators: |
Kircher, T.  ORCID: https://orcid.org/0000-0002-6494-1403, Pantsar, T. ORCID: https://orcid.org/0000-0002-0369-2909, Oder, A., von Kries, J.P. ORCID: https://orcid.org/0000-0003-4716-4988, Juchum, M., Pfaffenrot, B., Kloevekorn, P., Albrecht, W., Selig, R. ORCID: https://orcid.org/0000-0002-5375-2156 and Laufer, S. ORCID: https://orcid.org/0000-0001-6952-1486
|
| Abstract: | The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in liver regeneration and is under investigation as a target for stimulating hepatocytes to increased proliferation. Therefore, new small molecules inhibiting MKK4 may represent a promising approach for treating acute and chronic liver diseases. Fluorescently labeled compounds are useful tools for high-throughput screenings of large compound libraries. Here we utilized the azaindole-based scaffold of FDA-approved BRAF inhibitor vemurafenib 1, which displays off-target activity on MKK4, as a starting point in our fluorescent compound design. Chemical variation of the scaffold and optimization led to a selection of fluorescent 5-TAMRA derivatives which possess high binding affinities on MKK4. Compound 45 represents a suitable tool compound for Fluorescence polarization assays to identify new small-molecule inhibitors of MKK4. |
| Keywords: | Mitogen-Activated Protein Kinase Kinase 4, Vemurafenib, Fluorescence Polarization Assay |
| Source: | European Journal of Medicinal Chemistry |
| ISSN: | 0223-5234 |
| Publisher: | Elsevier |
| Volume: | 2019 |
| Page Range: | 112901 |
| Date: | 1 January 2021 |
| Additional Information: | Copyright © 2020 Elsevier Masson SAS. All rights reserved. |
| Official Publication: | https://doi.org/10.1016/j.ejmech.2020.112901 |
| External Fulltext: | View full text on external repository or document server |
| PubMed: | View item in PubMed |
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