Entinostat-Bortezomib Hybrids against Multiple Myeloma

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Pharmacology

Background:

• Proteasome inhibitors are crucial for multiple myeloma (MM) treatment but face challenges with drug resistance and relapse.
• Combination therapy with histone deacetylase (HDAC) inhibitors enhances anti-myeloma efficacy but presents pharmacokinetic/pharmacodynamic limitations.
• Hybrid molecules offer a strategy to overcome combination therapy drawbacks by integrating multiple pharmacophores into a single entity.

Purpose of the Study:

• To synthesize novel hybrid molecules integrating HDAC and proteasome inhibitor pharmacophores.
• To evaluate the antiproliferative and target inhibitory activities of these hybrids against multiple myeloma.
• To identify a lead compound with enhanced efficacy in preclinical models.

Main Methods:

• Synthesis of eleven hybrid molecules combining entinostat and bortezomib pharmacophores.
• Assessment of antiproliferative activity using IC50 values in RPMI 8226 MM cells and bortezomib-resistant variants.
• Evaluation in a 3D spheroid model incorporating MM and mesenchymal stem cells.
• Measurement of HDAC and proteasome inhibition activity.

Main Results:

• Compound 3 exhibited potent antiproliferative activity with IC50 values of 9.5 nM (RPMI 8226) and 157.7 nM (resistant cells).
• Compound 3 demonstrated efficacy in a 3D spheroid model (IC50: 13.1 nM), indicating activity in a more complex microenvironment.
• The compound inhibited HDAC activity by 33% and proteasome activity with an IC50 of 23.6 nM.

Conclusions:

• The synthesized HDAC-proteasome inhibitor hybrids represent a promising new class of anti-myeloma agents.
• Compound 3 shows significant potential as a therapeutic candidate for multiple myeloma, including resistant forms.
• Hybrid molecule design offers an effective approach to enhance anti-cancer activity and overcome drug resistance.