Carboxamide-Bearing Panobinostat Analogues Designed To Interact with E103-D104 at the Cavity Opening of Class I HDAC...

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Cancer Biology

Background:

• Panobinostat inhibits zinc-dependent histone deacetylases (HDACs), which are crucial targets in cancer therapy.
• Class I HDACs are implicated in various cancers, making them attractive targets for drug development.

Purpose of the Study:

• To synthesize and evaluate novel Panobinostat analogues incorporating carboxamide groups.
• To investigate the structure-activity relationship of these analogues concerning HDAC2 inhibition.
• To explore the potential for enhanced binding through hydrogen bond formation with acidic residues in the HDAC active site.

Main Methods:

• Synthesis of three sets of Panobinostat analogues featuring carboxamide functionalities.
• In vitro evaluation of synthesized analogues as inhibitors of HDAC2, determining IC50 values.
• Ensemble docking studies to predict binding modes and interactions within the HDAC2 active site.

Main Results:

• All synthesized Panobinostat analogues exhibited lower potency against HDAC2 (IC50 range: 150-3320 nM) compared to Panobinostat (IC50 = 5 nM).
• The most potent analogues, S-3 (IC50 = 150 nM) and S-2 (IC50 = 350 nM), formed hydrogen bonds with E103 and D104 via their carboxamide NH2 group.
• Reduced pKa values were observed in analogues due to the electron-withdrawing carboxamide group.
• Docking studies suggested that decreased electrostatic binding, solvation, and steric factors counteracted the benefits of increased hydrogen bonding.

Conclusions:

• The introduction of carboxamide groups into Panobinostat analogues did not enhance HDAC2 inhibitory potency.
• Hydrogen bond formation with acidic residues (E103, D104) was observed but insufficient to overcome reduced binding affinity.
• The synthesized analogues are unlikely to possess significant isoform selectivity for class I HDACs.