Computational Cell Cycle Profiling of Cancer Cells for Prioritizing FDA-Approved Drugs with Repurposing Potential

• Published in: Scientific reports Vol. 7; no. 1; pp. 11261 - 12
• Main Authors: Lo, Yu-Chen, Senese, Silvia, France, Bryan, Gholkar, Ankur A., Damoiseaux, Robert, Torres, Jorge Z.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2017; Nature Publishing Group
• Subjects: 631/80; 631/92/360; Cancer; Cell cycle; Computer applications; DNA damage; Drug development; Drug discovery; Drugs; FDA approval; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary); Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-11508-2

Discovery of first-in-class medicines for treating cancer is limited by concerns with their toxicity and safety profiles, while repurposing known drugs for new anticancer indications has become a viable alternative. Here, we have developed a new approach that utilizes cell cycle arresting patterns as unique molecular signatures for prioritizing FDA-approved drugs with repurposing potential. As proof-of-principle, we conducted large-scale cell cycle profiling of 884 FDA-approved drugs. Using cell cycle indexes that measure changes in cell cycle profile patterns upon chemical perturbation, we identified 36 compounds that inhibited cancer cell viability including 6 compounds that were previously undescribed. Further cell cycle fingerprint analysis and 3D chemical structural similarity clustering identified unexpected FDA-approved drugs that induced DNA damage, including clinically relevant microtubule destabilizers, which was confirmed experimentally via cell-based assays. Our study shows that computational cell cycle profiling can be used as an approach for prioritizing FDA-approved drugs with repurposing potential, which could aid the development of cancer therapeutics.