Identification of SET/EED dual binders as innovative PRC2 inhibitors
| Autor: | Raffaella Catalano, Annalisa Maruca, Roberta Rocca, Pierfrancesco Tassone, Giulia Panzarella, Giosuè Costa, Francesco Ortuso, Stefano Alcaro |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Future Medicinal Chemistry. 14:609-621 |
| ISSN: | 1756-8927 1756-8919 |
| DOI: | 10.4155/fmc-2022-0010 |
| Popis: | Background: The inhibition of PRC2, implicated in the pathogenesis of several tumors, can be a useful therapeutic strategy for cancer treatment. In the literature, two types of PRC2 modulators are reported: competitive inhibitors of S-adenosyl methionine binding to the catalytic subunit EZH2; and allosteric ligands that prevent the interaction of the trimethylated H3K27 lysine in histone 3 to the EED subunit. The lack of dual EZH2/EED modulators drove us to search for compounds capable of recognizing both domains. Materials & methods: This goal was pursued by combining pharmacophore- and docking-based virtual screening of the Multi-Target Ligand Chemotheca database. Prediction tools for absorption, distribution, metabolism and excretion and pan-assay interference compounds were also applied. Results: Finally, five 1,2,3-triazole derivatives were identified as promising dual EZH2/EED modulators. Conclusion: Our multistage screening protocol highlighted the great potential of Chemotheca for identifying polypharmacological agents. |
| Databáze: | OpenAIRE |
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