Recent developments in topoisomerase-targeted cancer chemotherapy

Abstract

The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA topology during DNA replication, and transcription are the targets of a wide range of antimicrobial and cancer chemotherapeutic agents. Natural product-derived agents, such as the camptothecin, anthracycline, and podophyllotoxin drugs, have seen broad use in the treatment of many types of cancer. Selective targeting of the topoisomerase enzymes for cancer treatment continues to be a highly active area of basic and clinical research. The focus of this review will be to summarize the current state of the art with respect to clinically used topoisomerase inhibitors for targeted cancer treatment and to discuss the pharmacology and chemistry of promising new topoisomerase inhibitors in clinical and pre-clinical development.

Keywords: ADP, adenosine diphosphate; AQD, anti-cancer quinolone derivative; ATP, adenosine triphosphate; Cancer; Clinical; DNA, deoxyribonucleic acid; Inhibition; MTD, maximum tolerated dose; NCI, National Cancer Institute; NCT, national clinical trial; Oncology; PD, pharmacodynamics; PFS, progression free survival; Pre-clinical; Topoisomerase.

Graphical abstract

Figure 1

Structures of human topoisomerases. Shown are the structures of the full length human topoisomerase I (left, PDB ID 1k4t) and topoisomerase IIα (right, PDB ID 5qwk) enzymes with bound DNA, representative of the overall structure and domains of the two sub-family types (DNA ribbon is colored yellow; chain A of topoisomerase I is blue; chain A of topoisomerase IIα is green; chain B of topoisomerase IIα is red).,

Figure 2

Etoposide binding to human topoisomerase IIα. Shown is the topoisomerase poison, etoposide, bound to the active site of human topoisomerase IIα. DNA is represented with yellow ribbons, yellow carbons, and filled rings. Protein is represented with cyan carbons, and the drug is shown with ball and stick representation with orange carbons. Hydrogen bonds to protein and DNA are shown as dashed yellow lines.

Figure 3

ATP binding site of Human Topoisomerase IIα. Depicted is the ATP binding site of the human topoisomerase IIα enzyme. ADP is bound to the binding site (yellow carbons) with hydrogen bonds to the protein shown in yellow, dashed lines. The active site residues are shown with cyan carbons and a translucent gray surface is used to show the shape of the binding site.

Figure 4

Structures of the marketed anthracycline topoisomerase inhibitors.

Figure 5

Structures of the marketed anthracenedione and acridine-derived topoisomerase inhibitors.

Figure 6

Structures of the camptothecin-derived topoisomerase inhibitors.

Figure 7

Structures of epipodophyllotoxin-derived topoisomerase inhibitors.

Figure 8

Representative topoisomerase inhibitors in clinical trials for cancer.

Figure 9

Preclinical topoisomerase inhibitors in recent literature.

Figure 10

Additional topoisomerase-active agents in recent literature.