DNA topoisomerase I

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DNA topoisomerase I

Catalog Product Name CAS Number
BADC-00607 DXD 1599440-33-1
DXD is a derivative of Exatecan, a topoisomerase I inhibitor. DXD is used in Trastuzumab deruxtecan.
BADC-00841 SN-38 86639-52-3
SN-38 (NK012) is an active metabolite of the Topoisomerase I inhibitor Irinotecan. SN-38 (NK012) inhibits DNA and RNA synthesis with IC50s of 0.077 and 1.3 μM, respectively.
BADC-00842 Rebeccamycin 93908-02-2
Rebeccamycin, an antitumor antibiotic, inhibits DNA topoisomerase I. Rebeccamycin appears to exert its primary antineoplastic effect by poisoning topoisomerase I and has negligible effect on protein k...
BADC-00044 Camptothecin 7689-03-4
Camptothecin (CPT) is a potent DNA enzyme topoisomerase I (topo I) inhibitor with an IC50 and IC70 of 50 nM and 0.225 μM for breast cancer cell line MDA-MB-231. Camptothecin is extratced from the bark...
BADC-00627 DRF-1042 200619-13-2
DRF-1042 is a DNA topoisomerase I inhibitor potentially for the treatment of solid tumors. DRF-1042 is an orally active derivative of Camptothecin. DRF-1042 acts to inhibit DNA topoisomerase I. DRF-10...

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Topoisomerases are essential enzymes that widely exist in organisms and participate in critical intranuclear processes such as DNA replication, transcription, recombination and reparation. Usually, topoisomerases are divided into DNA Topoisomerase I (Topo I) and DNA Topoisomerase II (Topo II) according to a different mechanism of DNA topoisomerases catalyzing DNA topoisomer transformation. Topo I affects the DNA topological structure by regulating superhelical, linkage, delinkage and unknotting effects. With a broad application of Camptothecins (CPTs) in clinical, Topo I has become an essential novel target for the research of anti-tumor drugs. The three CPTs drugs listed here are Irinotecan (CPT-11), Topotecan (TPT) and Hydroxycamptothecin (HCPT), and they were used in clinical treatment for colon cancer, ovarian cancer and lung cancer, respectively.

ADCs DNA Topoisomerase I Biochemistry 2009, 48, 14, 3176–3185.

DNA Topoisomerase I Characteristics

Topoisomerase I (Topo I) is a monomeric protein composed of 765 amino acids, including the N-terminal domain, core domain, linker domain, and carboxyl-terminal domain. The N-terminal domain is positively charged and contains minor hydrophobic amino acids. Thus it cannot form a stable spherical domain. The carboxyl-terminal domain, which includes a critical active site residue Tyr723, can be recombined with an independent core domain and achieve the activity that approximates the holoenzyme. Although the linker domain does not affect to the catalytic activity. It stabilizes the DNA downstream by forming hydrogen bonds with the nucleotides of DNA cleavage sites to slow down the reconnection process. The core domain contains all active site residues except Tyr723 (Arg488, Arg590, His632 and Lys532, etc.). Mechanistic research indicates that Topo I form a 3′-phosphotyrosine ester bond and 5′-hydroxy by nucleophilic attack on a single-stranded phosphodiester bond of DNA, and the broken single-stranded revolves around DNA to unlock the positive supercoil state and continue DNA replication.

DNA Topoisomerase I Inhibitor

Topoisomerase I (Topo I) inhibitors have become a vital target enzyme for designing new anti-cancer drugs. Such anti-cancer drugs have high efficacy and a broad anti-tumor spectrum. Moreover, the Topo I content of various tumor cells (especially colon cancer, cervical cancer, ovarian cancer) is much higher than that of normal tissues, especially in S-stage tumor cells. Therefore, drugs that inhibit Topo I can selectively inhibit DNA replication in proliferating tumor cells. The Topo I inhibitors are usually divided into Topo I poison and Topo I suppressor, which inhibit Topo I activity and prevent DNA relaxation. Topo I poison, which includes DNA intercalating agent, groove binders (minor-groove binders and major groove binders) and inhibitors that combine DNA with Topo I, can capture the Topo I-DNA cleavable complex and form a barrier that prevents DNA replication and leads to cell death. Topo I suppressor damage cells by inhibiting the catalytic activity of enzymes, so it contains higher activity in cells with low Topo I expression. Both Topo1 poison and Topo1 suppressor revealed potentials in anti-tumor therapy.

References

  1. Baker, N.M.; et al. Structural studies of type I topoisomerase. Nucleic Acids Res., 2015, 37(3): 693-701.
  2. Barros, F.W.; et al. Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives. Toxicol Appl Pharmacol., 2013, 268(1): 37-46.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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