Optimal linker length for small molecule PROTACs that selectively target p38a and p38B for degradation.
We report the design of hetero-bifunctional small molecules that selectively target p38a and p38B for degradation. These proteolysis targeted chimeras (PROTACs) are based on an ATP competitive inhibitor of p38a and p38B, which is linked to thalidomide analogues to recruit the Cereblon E3 ubiquitin ligase complex. Compound synthesis was facilitated ... by the use of a copper catalyzed click reaction. We show that optimization of the linker length and composition is crucial for the degradation-inducing activity of these PROTACs. We provide evidence that these chemical compounds can induce degradation of p38a and p38B but no other related kinases at nanomolar concentrations in several mammalian cell lines. Accordingly, the PROTACs inhibit stress and cytokine-induced p38 signaling. Our compounds contribute to understanding the development of PROTACs, and provide a useful tool to investigate functions of the p38 MAPK pathway and its involvement in diseases.
Mesh Terms:
Antineoplastic Agents, Cell Line, Tumor, HEK293 Cells, Humans, Ligands, Lymphoma, Large B-Cell, Diffuse, Peptide Hydrolases, Protein Binding, Proteolysis, Proto-Oncogene Proteins c-bcl-6, Quinolones, Thalidomide, Ubiquitin-Protein Ligases
Antineoplastic Agents, Cell Line, Tumor, HEK293 Cells, Humans, Ligands, Lymphoma, Large B-Cell, Diffuse, Peptide Hydrolases, Protein Binding, Proteolysis, Proto-Oncogene Proteins c-bcl-6, Quinolones, Thalidomide, Ubiquitin-Protein Ligases
Eur J Med Chem
Date: Sep. 01, 2020
PubMed ID: 32634680
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