Selective CDK9 Inhibition by Natural Compound Toyocamycin in Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Aberrant gene transcription, including tumor suppressor gene (TSG) silencing and oncogene activation, is a hallmark of cancer.
• Epigenomic alterations like DNA hypermethylation and histone deacetylation silence TSGs.
• Novel therapeutic strategies are needed to reactivate TSGs in cancer cells.

Purpose of the Study:

• To screen for natural products that induce TSG reactivation in cancer cells.
• To identify the molecular mechanism of action for identified compounds.
• To evaluate the therapeutic potential of these compounds in cancer chemotherapy.

Main Methods:

• Utilized a GFP-reporter system to identify compounds inducing TSG reactivation.
• Screened a natural product drug library.
• Performed connectivity-mapping, RNA-sequencing, kinase assays, and molecular docking.

Main Results:

• Identified toyocamycin, an adenosine analog, that induces GFP reactivation and loss of clonogenicity in colon cancer cells.
• Toyocamycin's pharmacological signature mimics cyclin-dependent kinase (CDK) inhibitors, specifically CDK9.
• Toyocamycin potently and specifically inhibits CDK9 (IC50 = 79 nM) with greater efficacy than other CDKs.

Conclusions:

• Toyocamycin specifically inhibits CDK9 in cancer cells.
• Toyocamycin demonstrates potential as a novel therapeutic agent for cancer chemotherapy by reactivating TSGs.