Discovery of Pyrimidoindolones as Novel Family VIII Bromodomain Binders

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Aberrant gene expression drives cancer, making oncogene suppression a key therapeutic strategy.
• The SWI/SNF (SWItch/Sucrose Non-Fermentable) complex regulates gene transcription; its dysregulation is implicated in various cancers.
• Specific subunits of the SWI/SNF complex, including SMARCA2, SMARCA4, and PBRM1 (bromodomain family VIII), are promising therapeutic targets.

Purpose of the Study:

• To identify novel small molecules targeting bromodomain family VIII proteins.
• To discover and optimize new chemical entities for cancer therapy.

Main Methods:

• Utilized NMR-based fragment screening to identify initial binders.
• Employed medicinal chemistry optimization to enhance binding affinity and drug-like properties.

Main Results:

• Discovered pyrimidoindolones as a novel class of bromodomain family VIII binders.
• Achieved sub-micromolar affinity for SMARCA2, SMARCA4, and PBRM1.
• Developed compounds with favorable physicochemical properties for potential therapeutic development.

Conclusions:

• Pyrimidoindolones represent a promising new scaffold for targeting bromodomain family VIII proteins.
• These findings offer a potential new avenue for cancer treatment by modulating SWI/SNF complex activity.