Efficient hit-finding approaches for histone methyltransferases: the key parameters.

Area of Science:

• Epigenetics
• Medicinal Chemistry
• Drug Discovery

Background:

• Limited chemical and structural data for novel epigenetic targets necessitate large screening libraries.
• Histone methyltransferase G9a is a key epigenetic target with largely unknown ligand space.

Purpose of the Study:

• To develop an efficient hit-finding strategy for epigenetic targets using virtual screening.
• To identify novel chemotypes for the histone methyltransferase G9a.

Main Methods:

• Applied virtual screening methods for intelligent compound selection from a 900,000-compound library.
• Utilized FlashPlate assay with histone H3.1 substrate for primary screening of 2112 compounds.
• Validated hits using orthogonal fluorescence lifetime technology.

Main Results:

• Identified 18 validated G9a hits (0.9% of screened deck) with high purity and favorable IC50 values.
• Discovered novel chemotypes, advancing hit-to-lead projects.
• Demonstrated the efficacy of virtual screening for epigenetic targets.

Conclusions:

• Virtual screening significantly enhances hit identification for challenging epigenetic targets.
• The developed approach provides a powerful tool for discovering therapeutics for epigenetic diseases.
• Novel G9a inhibitors pave the way for future drug development.