Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• SWI/SNF (BAF) complexes are ATP-dependent chromatin remodelers crucial for cell viability.
• Mutations in BAF complexes are implicated in 20% of human cancers and neurological diseases.
• Direct inhibition of BAF complexes is limited by potential toxicity due to their essential gene-activating roles.

Purpose of the Study:

• To identify therapeutic strategies targeting the repressive functions of BAF complexes.
• To circumvent the toxicity associated with general SWI/SNF inhibition.
• To explore the synergistic effects of novel small molecules with ATR inhibitors in cancer treatment.

Main Methods:

• Screening for small molecules that specifically inhibit the repressive function of BAF complexes.
• Assessing the toxicity profiles of identified small molecules.
• Evaluating the synergy between these small molecules and ATR inhibitors in cancer cell killing assays.

Main Results:

• Identification of novel small molecules that selectively inhibit BAF complex repressive functions.
• Demonstration that these molecules are relatively non-toxic compared to general BAF inhibitors.
• Significant synergy observed between these small molecules and ATR inhibitors in eradicating cancer cells.

Conclusions:

• Targeting the specific repressive function of BAF complexes offers a safer therapeutic avenue.
• Chemical synthetic lethality involving BAF complexes presents a promising strategy for cancer therapy.
• This approach enhances the therapeutic potential of ATR/ATM inhibition in oncology.