350 rub
Journal №3 for 2015 г.
Article in number:
Inhibitors of DNA repair enzymes as prototypes of medicinal preparations
Keywords: DNA repair poly (ADP-ribose) polymerase tyrosyl-DNA phosphodiesterase inhibitoz
Authors:
A.L. Zakharenko -Ph.D.(Chem.), Research Scientist, Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (Novosibirsk). E-mail: sashaz@niboch.nsc.ru N.I. Rechkunova - Ph.D.(Chem.), Senior Research Scientist, Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (Novosibirsk); Associate Professor, Novosibirsk State University (Novosibirsk). E-mail: nadyarec@niboch.nsc.ru O.I. Lavrik - Dr.Sc.(Chem.), Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (Novosibirsk); Professor, Novosibirsk State University (Novosibirsk). E-mail: lavrik@niboch.nsc.ru
Abstract:
The DNA damage response, consisting of an organized network of proteins implementing repair and cell cycle arrest has arisen during the evolution to keep the cell viability and to prevent the damaged DNA transfer to daughter cells. The DNA damage response is dysregulated in cancer cells with some pathways being up-regulated and others down-regulated or lost. Up-regulated pathways can confer resistance to anti-cancer DNA damaging agents. Therefore, inhibition of key enzymes of these pathways could prevent this therapeutic resistance. Vice-versa, defects in an individual DNA damage response pathway may lead to dependence on a complementary pathway. Inhibition of this complementary pathway may result in tumor-specific cell killing. Thus, inhibitors of the DNA damage response have the potential to increase the efficacy of chemotherapy and radiotherapy and have single-agent activity against tumors with a specific DNA damage response defect. Poly(ADP-ribose)polymerase 1 (PARP1) is the enzyme involved in multiple cellular processes such as transcription, replication, DNA repair and cell death. PARP1 is regarded as a promising target in cancer therapy. There are 8 PARP1 inhibitors in clinical trials today, both as monotherapy, and in combination with other anticancer drugs [1]. There exists a problem of PARP1 selectivity. This enzyme is a member of the family consisting of 17 proteins containing conserved catalytic domain. Recent studies revealed that many of the best-known inhibitors suppressed the activity of several PARP family members [2]. Therefore it is of interest the search of selective inhibitors of PARP2, another DNA repair factor. This enzyme is involved in lesser row of processes than PARP1, allowing to expect creation of pharmaceuticals which selectively suppresses DNA repair but doesn-t affect other PARP1 functions. Another promising therapeutic target is tyrosyl-DNA phosphodiesterase 1 (Tdp1), - recently discovered enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Top1-DNA covalent adducts are normal transition state in the catalytic cycle of Top1 but may be stabilized by DNA damage or anticancer drugs such as camptothecin By reducing the repair of Top1-DNA lesions, Tdp1 inhibitors can potentially increase the anticancer activity of Top1 inhibitors. Targeting the DNA repair is a promising strategy for cancer therapy, both to reduce resistance to DNA damaging anti-cancer therapy and also to specifically target defects in the DNA damage response.
Pages: 26-44
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