Journal
ACS CHEMICAL BIOLOGY
Volume 8, Issue 1, Pages 82-95Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb300648v
Keywords
-
Categories
Funding
- Center for Cancer Research [Z01 BC 0006161]
- National Cancer Institute
- NATIONAL CANCER INSTITUTE [ZIABC006161, Z01BC006161, ZIABC006150] Funding Source: NIH RePORTER
Ask authors/readers for more resources
Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. They are essential during transcription and replication, and topoisomerase inhibitors are among the most effective and most commonly used anticancer and antibacterial drugs. This review consists of two parts. In the first part (Lessons), it gives background information on the catalytic mechanisms of the different enzyme families (6 different genes in humans and 4 in most bacteria), describes the interfacial inhibition by which topoisomerase-targeted drugs act as topoisomerase poisons, and describes clinically relevant topoisomerase inhibitors. It generalizes the interfacial inhibition principle, which was discovered from the mechanism of action of topoisornerase inhibitors, and discusses how topoisomerase inhibitors kill cells by trapping topoisomerases on DNA rather than by classical enzymatic inhibition. Trapping protein DNA complexes extends to a novel mechanism of action of PARP inhibitors and could be applied to the targeting of transcription factors. The second part of the review focuses on the challenges for discovery and precise use of topoisomerase inhibitors, including targeting topoisornerase inhibitors using chemical coupling and encapsulation for selective tumor delivery, use of pharmacodynarnic biomarkers to follow drug activity, complexity of the response determinants for anticancer activity and patient selection prospects of rational combinations with DNA repair inhibitors targeting tyrosyl-DNA-phosphodiesterases 1 and 2 (TDP1 and TDP2) and PARP, and the unmet need to develop inhibitors for type IA enzymes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available