Type II Topoisomerase - Inhibition

Inhibition

Small molecules that target type II topoisomerase are divided into two classes: inhibitors and poisons.

• Inhibitors of type II topoisomerase include HU-331, ICRF-187, ICRF-193, and mitindomide. These molecules work by inhibiting the ATPase activity by acting as noncompetitive inhibitors of ATP. This has been shown through structural studies (Classen et al. Proceedings of the National Academy of Science, 2005) and biochemical studies performed by the Lindsley group.

• Poisons of type II topoisomerases include etoposide, novobiocin, quinolones (including ciprofloxacin), and teniposide. These small molecules target the DNA-protein complex. Some of these molecules lead to increased cleavage, whereas others, such as etoposide, inhibit religation.

The experimental antitumor drug m-AMSA (4'-(9'-acridinylamino)methanesulfon-m-anisidide) also inhibits type 2 topoisomerase.

Topoisomerase poisons have been extensively used as both anticancer and antibacterial therapies. While antibacterial compounds such as ciprofloxacin target bacterial gyrase, they fail to inhibit eukaryotic type IIA topoisomerases. In addition, drug-resistant bacteria often have a point mutation in gyrase (Serine79Alanine in E. coli) that renders quinolones ineffective. Recent structural studies have led to the discovery of a compound that no longer relies on this residue and, therefore, has efficacy against drug-resistant bacteria.