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Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4

Item Type:Article
Title:Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4
Creators Name:Kircher, T. and Pantsar, T. and Oder, A. and von Kries, J.P. and Juchum, M. and Pfaffenrot, B. and Kloevekorn, P. and Albrecht, W. and Selig, R. and Laufer, S.
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
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
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