Identification of SET/EED dual binders as innovative PRC2 inhibitors

Author:

Catalano Raffaella12ORCID,Maruca Annalisa12ORCID,Rocca Roberta23ORCID,Tassone Pierfrancesco3ORCID,Panzarella Giulia1ORCID,Costa Giosuè12ORCID,Ortuso Francesco12ORCID,Alcaro Stefano12ORCID

Affiliation:

1. Dipartimento di Scienze della Salute, Campus ‘S. Venuta’, Università ‘Magna Græcia’ di Catanzaro, Viale Europa, Catanzaro, 88100, Italy

2. Net4Science Academic Spin-Off, Campus ‘S. Venuta’, Università ‘Magna Græcia’ di Catanzaro, Viale Europa, Catanzaro, 88100, Italy

3. Dipartimento di Medicina Sperimentale e Clinica, Campus ‘S. Venuta’, Università ‘Magna Græcia’ di Catanzaro, Viale Europa, Catanzaro, 88100, Italy

Abstract

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.

Funder

Associazione Italiana per la Ricerca sul Cancro

Ministero dell'Istruzione, dell'Università e della Ricerca

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

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