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Entinostat-Bortezomib Hybrids against Multiple Myeloma.
Ferro, Angelica; Graikioti, Dafni; Gezer, Emre; Athanassopoulos, Constantinos M; Cuendet, Muriel.
Afiliação
  • Ferro A; School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland.
  • Graikioti D; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland.
  • Gezer E; Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, 26504 Patras, Greece.
  • Athanassopoulos CM; School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland.
  • Cuendet M; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland.
Molecules ; 28(3)2023 Feb 02.
Article em En | MEDLINE | ID: mdl-36771118
Although proteasome inhibitors have emerged as the therapeutic backbone of multiple myeloma treatment, patients often relapse and become drug refractory. The combination between proteasome and histone deacetylase inhibitors has shown to be more efficient compared to monotherapy by enhancing the anti-myeloma activity and improving the patient's lifetime expectancy. Hybrid molecules, combining two drugs/pharmacophores in a single molecular entity, offer improved effectiveness by modulating more than one target and circumventing differences in the pharmacokinetic and pharmacodynamic profiles, which are the main disadvantages of combination therapy. Therefore, eleven histone deacetylase-proteasome inhibitor hybrids were synthesized, combining pharmacophores of entinostat and bortezomib. Compound 3 displayed the strongest antiproliferative activity with an IC50 value of 9.5 nM in the multiple myeloma cells RPMI 8226, 157.7 nM in the same cell line resistant to bortezomib, and 13.1 nM in a 3D spheroid model containing multiple myeloma and mesenchymal stem cells. Moreover, the compound inhibited 33% of histone deacetylase activity when RPMI 8226 cells were treated for 8 h at 10 µM. It also inhibited the proteasome activity with an IC50 value of 23.6 nM.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mieloma Múltiplo / Antineoplásicos Limite: Humans Idioma: En Revista: Molecules Assunto da revista: BIOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mieloma Múltiplo / Antineoplásicos Limite: Humans Idioma: En Revista: Molecules Assunto da revista: BIOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suíça