Tracing MYC Expression for Small Molecule Discovery

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Targeting MYC, a key oncogene, remains challenging for cancer therapeutics.
• Existing methods for monitoring MYC expression are insufficient for drug screening.

Purpose of the Study:

• To develop a novel phenotype-based assay for monitoring MYC expression in multiple myeloma cells.
• To identify novel MYC expression modulators using a high-throughput screening approach.

Main Methods:

• Engineered co-expression of MYC and an unstable variant of GFP using CRISPR/Cas9 at the endogenous MYC locus.
• Implemented a fluorescence readout as a surrogate for MYC expression.
• Conducted a pilot screen of approximately 10,000 compounds.

Main Results:

• Successfully established a CRISPR/Cas9-engineered MYC expression assay.
• Identified cardiac glycosides and cytoskeletal disruptors as potent inhibitors of MYC expression.
• Demonstrated the utility of this assay for identifying gene expression modulators.

Conclusions:

• CRISPR/Cas9 engineering provides a powerful platform for developing phenotype-based drug discovery assays.
• The developed assay enables efficient screening for MYC expression modulators.
• Novel classes of compounds, including cardiac glycosides, show potential for targeting MYC-driven cancers.