Peptidomimetic Polo-Box targeted inhibitors that engage PLK1 in tumor cells and are selective against the PLK3 tumor suppressor
| Autor: | Michael D. Wyatt, Sandra Craig, Merissa Baxter, Jessy Varghese, Danda Chapagai, Campbell McInnes, Cecilia Hurtado, Elmar Nurmemmedov |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Peptidomimetic
Cell Cycle Proteins Protein Serine-Threonine Kinases 01 natural sciences Biochemistry PLK1 behavioral disciplines and activities Article Protein–protein interaction Structure-Activity Relationship Protein Domains Proto-Oncogene Proteins Drug Discovery Humans General Pharmacology Toxicology and Pharmaceutics Binding site Pharmacology Molecular Structure 010405 organic chemistry Phosphopeptide Kinase Chemistry Tumor Suppressor Proteins Organic Chemistry Tumor Protein Translationally-Controlled 1 Subcellular localization 0104 chemical sciences Cell biology Molecular Docking Simulation 010404 medicinal & biomolecular chemistry PC-3 Cells Molecular Medicine Phosphorylation Peptidomimetics Peptides Protein Binding |
| Zdroj: | ChemMedChem |
| Popis: | The polo-box domain (PBD) of PLK1 determines mitotic substrate recognition and subcellular localization. Compounds that target PLK1 selectively are required due to the tumor-suppressor roles of PLK3. A structure-activity analysis of the PBD phosphopeptide binding motif has identified potent peptides that delineate the determinants required for mimicry by nonpeptidic inhibitors and provide insights into the structural basis for the selectivity of inhibitors for the PLK1 PBD. Fragment-ligated inhibitory peptides (FLIPs) obtained through REPLACE have been optimized to enhance in vitro binding and a systematic analysis of selectivity for PLK1 vs PLK3 has been carried out for peptides and peptidomimetics. Furthermore, these more drug-like non-ATP-competitive inhibitors had on-target engagement in a cellular context, as evidenced by stabilization of PLK1 in a thermal-shift assay and by inhibition of the phosphorylation of TCTP, a target of PLK1. Investigation in cells expressing a mutant PLK1 showed that these cells are sensitive to PBD inhibitors but dramatically resistant to clinically investigated ATP-competitive compounds. These results further validate targeting the PBD binding site in the move towards PLK1 inhibitors that are active against tumors resistant to ATP inhibitors. |
| Databáze: | OpenAIRE |
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