Summary of the probe development effort to identify inhibitors of human tyrosyl-DNA phosphodiesterase 2 (TDP2)
Name: Summary of the probe development effort to identify inhibitors of human tyrosyl-DNA phosphodiesterase 2 (TDP2) ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Center Affiliation: The Scripps Research Institute (TSRI)
Assay Provider: Sanjay Adhikari, Georgetown University
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R03 DA035193-01A1
Grant Proposal PI: Sanjay Adhikari
External Assay ID: TDP2_INH_SUMMARY
Name: Summary of the probe development effort to identify inhibitors of human tyrosyl-DNA phosphodiesterase 2 (TDP2)
The TopoisomeraseII (TopII) family is an important class of topoisomerases that produces transient 5? DNA-protein crosslinks [1, 2]. Drugs targeting these enzymes act by stabilizing the crosslinks, producing a covalent DNA-protein complex [3, 4]. Despite their clinical efficacy, drugs that target TopII (TopII poisons) may lead to negative side-effects, including secondary malignancies. The repair of TopII-DNA complexes is poorly understood. Recently, a human 5?- tyrosine phosphodiesterase (hTDP2) has been identified for the excision of TopII-DNA adducts [5, 6]. As hTDP2 repairs the cytotoxic adducts produced by TopII poisons, it is likely that effective inhibition of hTDP2 can be targeted to improve the efficacy of TopII poisons and reduce the side-effects. It has been shown that the knockdown/knockout of TDP2 activity in A549 (non-small cell lung cancer cell line, NSCLC) and DT40 cells increased sensitivity to the TopII targeting agent etoposide, demonstrating that hTDP2 can be a target for adjuvant chemotherapy . Our hypothesis is effective inhibition of hTDP2 will increase the cancer cell killing efficacy of TopII poisons like etoposide . Therefore, hTDP2 inhibitor screening, especially in a high-throughput manner, will expedite drug discovery.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of human tyrosyl-DNA phosphodiesterase 2 (TDP2). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
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2. Wang, J.C., Moving one DNA double helix through another by a type II DNA topoisomerase: the story of a simple molecular machine. Q Rev Biophys, 1998. 31(2): p. 107-44. PMID 9794033.
3. Cutts, S.M., et al., The power and potential of doxorubicin-DNA adducts. IUBMB Life, 2005. 57(2): p. 73-81. PMID 16036566
4. Habermeyer, M., et al., Anthocyanidins modulate the activity of human DNA topoisomerases I and II and affect cellular DNA integrity. Chem Res Toxicol, 2005. 18(9): p. 1395-404. PMID 16167831
5. Cortes Ledesma, F., et al., A human 5'-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature, 2009. 461(7264): p. 674-8. PMID 19794497.
6. Bahmed, K., K.C. Nitiss, and J.L. Nitiss, UnTTrapping the ends: a new player in overcoming protein linked DNA damage. Cell Res, 2010. 20(2): p. 122-3. PMID 20118967.
7. Zeng, Z., et al., TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. J Biol Chem, 2011. 286(1): p. 403-9. PMID 21030584.
8. Bandele, O.J., S.J. Clawson, and N. Osheroff, Dietary polyphenols as topoisomerase II poisons: B ring and C ring substituents determine the mechanism of enzyme-mediated DNA cleavage enhancement. Chem Res Toxicol, 2008. 21(6): p. 1253-60. PMID 18461976.
9. Adachi, N., et al., Hypersensitivity of nonhomologous DNA end-joining mutants to VP-16 and ICRF-193: implications for the repair of topoisomerase II-mediated DNA damage. J Biol Chem, 2003. 278(38): p. 35897-902. PMID 12842886.
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