Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4
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CitationKircher, Theresa. Pantsar, Tatu. Oder, Andreas. Peter von Kries, Jens. Juchum, Michael. Pfaffenrot, Bent. Kloevekorn, Philip. Albrecht, Wolfgang. Selig, Roland. Laufer, Stefan. (2021). Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4. European journal of medicinal chemistry, 209, 112901. 10.1016/j.ejmech.2020.112901.
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.
Subjectsmitogen-activated protein kinase kinase 4 vemurafenib fluorescence polarization assay
Link to the original itemhttp://dx.doi.org/10.1016/j.ejmech.2020.112901
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