Structure-based optimization of click-based histone deacetylase inhibitors

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Histone deacetylases (HDACs) are crucial targets in various diseases, including cancer.
• Previous work established a click-chemistry approach for novel HDAC inhibitor synthesis.
• The lead compound NSC746457 exhibited potency comparable to SAHA (Vorinostat).

Purpose of the Study:

• To optimize the lead compound NSC746457 for enhanced histone deacetylase (HDAC) inhibition.
• To explore structure-activity relationships by targeting the HDAC2 binding domain.
• To identify novel, more potent HDAC inhibitors through structural modifications.

Main Methods:

• Utilized the HDAC2-trichostatin A (TSA) crystal structure for rational drug design.
• Employed molecular docking to analyze interactions within the HDAC2 binding domain.
• Synthesized and characterized novel HDAC inhibitors with modifications in the cinnamic cap region.

Main Results:

• Molecular docking revealed Phe210 as a key residue for exploiting hydrophobic interactions.
• Structural optimization led to the synthesis of isopropyl derivative 5 and tert-butyl derivative 6.
• Compound 5 exhibited an IC(50) of 22 nM, and compound 6 showed an IC(50) of 18 nM against HDAC2.

Conclusions:

• The optimized HDAC inhibitors demonstrate significantly improved potency compared to the lead compound.
• Structural modifications targeting the HDAC2 binding pocket are effective for enhancing inhibitory activity.
• These findings provide a basis for developing novel therapeutic agents targeting HDACs.