title: Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) inhibitors.
abstract: Inhibitors of topoisomerase I (Top1) that result in stalled Top1 cleavage complexes (Top1cc) are commonly employed against cancer. Combination chemotherapy with DNA repair inhibitors can potentially improve response to these widely used chemotherapeutics. One line of inquiry focuses on inhibitors of tyrosyl-DNA phosphodiesterase 1 (Tdp1), a repair enzyme for Top1cc. Tdp1 catalyzes the hydrolysis of DNA adducts covalently linked to the 3'-phosphate of DNA, including Top1-derived peptides and also 3'-phosphoglycolates. Tdp1 inhibitors should synergize not only with Top1-targeting drugs (camptothecins, indenoisoquinolines), but also with bleomycin, topoisomerase II (Top2) inhibitors (etoposide, doxorubicin) and DNA alkylating agents. Here, we summarize the structure-activity relationship obtained from the reported Tdp1 inhibitors. Better understanding of Top1cc repair in vivo coupled with detailed structural studies on Tdp1-inhibitor interaction will be crucial in guiding the rational design of Tdp1 inhibitors.
authors.affiliation: National Cancer Institute , Center for Cancer Research, Laboratory of Molecular Pharmacology , National Institutes of Health , Bethesda, MD, 20892 , USA.
authors.forename: Shar-yin N
authors.initials: SN
authors.lastname: Huang
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000494:pharmacology; D032701:Biomimetics; D018736:DNA Adducts; D006801:Humans; D008958:Models, Molecular; D010330:Patents as Topic; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D012270:Ribosomes / Q000187:drug effects; D013754:Tetracyclines / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001550:Benzamidines; D018736:DNA Adducts; D010726:Phosphodiesterase Inhibitors; D013754:Tetracyclines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C033286:furamidine; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human