Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential

  • Bioorg Med Chem. 2016 Nov 1;24(21):5017-5027. doi: 10.1016/j.bmc.2016.09.045.
Sergey S Laev  1 ,  Nariman F Salakhutdinov  2 ,  Olga I Lavrik  3
Affiliations
  • 1. Vorozhtsov Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 9, Novosibirsk 630090, Russian Federation. Electronic address: [email protected].
  • 2. Vorozhtsov Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 9, Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova Str. 2, Novosibirsk 630090, Russian Federation.
  • 3. Novosibirsk State University, Pirogova Str. 2, Novosibirsk 630090, Russian Federation; Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 8, Novosibirsk 630090, Russian Federation.
PMID: 27687971 DOI: 10.1016/j.bmc.2016.09.045
Abstract

DNA topoisomerases are essential during transcription and replication. The therapeutic mechanism of action of Topoisomerase inhibitors is enzyme poisoning rather than catalytic inhibition. Tyrosyl-DNA phosphodiesterases 1 or 2 were found as DNA repair Enzymes hydrolyzing the covalent bond between the tyrosyl residue of topoisomerases I or II and the 3'- or 5'-phosphate groups in DNA, respectively. Tyrosyl-DNA phosphodiesterase 1 is a key enzyme in DNA repair machinery and a promising target for antitumor and neurodegenerative therapy. Inhibitors of tyrosyl-DNA phosphodiesterase 1 could act synergistically with Topoisomerase I inhibitors and thereby potentiate the effects of Topoisomerase I poisons. Tyrosyl-DNA phosphodiesterase 2 is an enzyme that specifically repairs DNA damages induced by Topoisomerase II poisons and causes resistance to these drugs. Selective inhibition of tyrosyl-DNA phosphodiesterase 2 may be a novel approach to overcome intrinsic or acquired resistance to Topoisomerase II-targeted drug therapy. Thus, agents that inhibit tyrosyl-DNA phosphodiesterases 1 and 2 have many applications in biochemical and physiological research and they have the potential to become Anticancer and Antiviral drugs. The structures, mechanism of action and therapeutic rationale of tyrosyl-DNA phosphodiesterase inhibitors and their development for combinations with Topoisomerase inhibitors and DNA damaging agents are discussed.

Keywords
Camptothecin; DNA repair; Indenoisoquinolines; Tdp1; Tdp1 inhibitors; Tdp2; Tdp2 inhibitors; Top1 inhibitors; Top2 inhibitors; Topoisomerase; Tyrosyl-DNA phosphodiesterase.
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