Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery

Area of Science:

• Genomics
• Molecular Biology
• Drug Discovery

Background:

• Genomics technologies have advanced understanding of cancer biology but not drug discovery.
• Global approaches are needed to discover new medicines for human diseases.

Purpose of the Study:

• To develop a high-throughput sequencing (HTS²) strategy for drug discovery.
• To identify small molecules targeting disease-linked gene expression.
• To apply this strategy to hormone-refractory prostate cancer.

Main Methods:

• Developed a high-throughput screening strategy by high-throughput sequencing (HTS²).
• Applied the multitarget strategy to hormone-refractory prostate cancer.
• Screened for small molecules intervening with disease-linked gene-expression events.

Main Results:

• Identified Peruvoside, a cardiac glycoside, inhibiting both androgen-sensitive and -resistant prostate cancer cells.
• Peruvoside demonstrated potent inhibition without severe cytotoxicity.
• Showed Peruvoside blocks androgen receptor-dependent gene expression by inducing rapid androgen receptor degradation via the proteasome pathway.

Conclusions:

• HTS² is a powerful genomics-based phenotypic screening approach for drug discovery.
• This approach connects phenotypic response pathways to drug action mechanisms.
• Offers a unique pathway-centric strategy for discovering novel therapeutics, exemplified by Peruvoside for prostate cancer.