Current Research in Polypharmacology for Cancer Treatment Using Dual-Target Histone Deacetylase Inhibitors

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Histone deacetylases (HDACs) are a key target in cancer therapy.
• Targeting multiple proteins simultaneously (polypharmacology) offers potential for improved antitumor activity.
• Recent research focuses on dual-target agents combining HDAC inhibition with other oncogenic pathways.

Purpose of the Study:

• To review recent advancements in dual-target antitumor agents over the past five years.
• To analyze agents targeting histone deacetylases (HDACs) and various membrane/nuclear proteins.
• To evaluate the efficacy, selectivity, and molecular design of these dual inhibitors.

Main Methods:

• Comprehensive literature review of studies on dual-target agents.
• Analysis of in vitro cytotoxicity assays against neoplastic and healthy cells.
• Inclusion of in vivo experiments (tumor volume in mice) and oral bioavailability assessments.

Main Results:

• Several dual inhibitors demonstrate superior in vitro cytotoxicity compared to monofunctional agents.
• Identified molecular fragments responsible for inhibiting specific targets (HDACs and others like PI3K, ALK, HER2, VEGFR2, Wee1, DNMT, CDC25A, CDK9, DYRK2, BRD4).
• Some dual agents exhibit enhanced selectivity towards tumor cells.

Conclusions:

• Dual-target agents show promising antitumor activity and selectivity.
• These findings support the use of polypharmacology for designing novel anticancer drugs.
• Further development of dual inhibitors could lead to more effective cancer therapies.