Design and synthesis of novel quinazoline derivatives as KDM6B selective inhibitors

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Histone lysine demethylase 6B (KDM6B) dysfunction is implicated in various diseases, including cancer and inflammatory conditions.
• KDM6B is a significant therapeutic target, but potent and selective inhibitors are lacking.
• Developing novel KDM6B inhibitors is crucial for advancing therapeutic strategies.

Purpose of the Study:

• To design, synthesize, and identify novel KDM6B inhibitors based on a hit compound.
• To evaluate the potency and selectivity of synthesized compounds against KDM6B.
• To assess the cellular effects of the most promising KDM6B inhibitor.

Main Methods:

• Hit compound A01-based scaffold hopping and derivatization using a quinazoline core.
• Enzyme inhibition assays to determine IC50 values and selectivity profiling against JMJD subfamily members.
• Cellular assays using THP-1 cells to assess the impact on histone methylation levels.

Main Results:

• A series of quinazoline derivatives were synthesized, exhibiting KDM6B inhibitory activity.
• Compound 13k demonstrated optimal potency (IC50 = 1.8 μM) and superior selectivity.
• Compound 13k effectively upregulated histone methylation levels in THP-1 cells.

Conclusions:

• The quinazoline scaffold represents a promising platform for developing selective KDM6B inhibitors.
• Compound 13k serves as a valuable tool compound for further research into KDM6B biological functions.
• These findings provide a potential lead for future KDM6B-targeted drug discovery efforts.