Entinostat-Bortezomib Hybrids against Multiple Myeloma.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Multiple Myeloma*/drug therapy ; Multiple Myeloma*/metabolism ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/therapeutic use; Humans ; Bortezomib/pharmacology ; Bortezomib/therapeutic use ; Proteasome Endopeptidase Complex/metabolism ; Boronic Acids/pharmacology ; Cell Line, Tumor ; Neoplasm Recurrence, Local/drug therapy ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/therapeutic use ; Histone Deacetylase Inhibitors/therapeutic use ; Histone Deacetylases ; Drug Resistance, Neoplasm

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 IC 50 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 IC 50 value of 23.6 nM.

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Keywords: HDAC inhibitors; drug resistance; hybrid inhibitors; multiple myeloma; proteasome inhibitors

69G8BD63PP (Bortezomib)
0 (Antineoplastic Agents)
1ZNY4FKK9H (entinostat)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
0 (Boronic Acids)
0 (Proteasome Inhibitors)
0 (Histone Deacetylase Inhibitors)
EC 3.5.1.98 (Histone Deacetylases)

Date Created: 20230211 Date Completed: 20230214 Latest Revision: 20230214

20240628

PMC9920246

10.3390/molecules28031456

36771118