Abstract
Thymidine kinase 2 (TK2), encoded on chromosome 16q22 of the human genome, is a deoxynucleoside kinase (dNK) that catalyzes the phosphorylation of the pyrimidine deoxynucleosides 2’-deoxythymidine (dThd), 2’-deoxyuridine (dUrd) and 2’- deoxycytidine (dCyd) to the corresponding deoxynucleoside 5’-monophosphate derivatives. In contrast to the S-phase-specific thymidine kinase 1 (TK1), TK2 is constitutively expressed in the mitochondria and plays an important role in providing dNTPs for the replication and maintenance of mitochondrial DNA (mtDNA). The severe mitochondrial DNA depletion syndrome (MDS) has been associated with mutations in TK2, resulting in mtDNA depletion, isolated skeletal myopathy, and death of the individual at an early stage of life. Some antiviral nucleoside analogs, such as 3’-azido-dThd (AZT) that is targeting the human immunodeficiency virus (HIV)-encoded reverse transcriptase, are substrates for TK2 and it has been proposed that the mitochondrial toxicity observed after prolonged treatment with such drugs could be due to their interaction with TK2. Therefore, the design of specific TK2 inhibitors may be useful to investigate the role of TK2 in the maintenance and homeostasis of mitochondrial dNTP pools and its contribution to the mitochondrial toxicity of several antiviral and anticancer drugs. Since 2000, several potent and selective TK2 inhibitors have been described. Besides bringing together previously reported inhibitors, special attention will be paid in this review to the new families of TK2 inhibitors more recently described, together with modeling studies and biological assays. Moreover, the last section will be focused on several recent investigations that suggest that depletion of mtDNA can take place both in tumorigenesis and during cancer treatment with certain nucleoside analogues.
Keywords: Mitochondrial thymidine kinase 2 (TK2), nucleoside metabolism, enzymatic inhibitors, mitochondrial depletion syndrome (MDS), tumorigenesis, chromosome 16q22, deoxynucleoside kinase (dNK), reverse transcriptase, cancer treatment, nucleoside analogues
Current Pharmaceutical Design
Title:Recent Advances in Thymidine Kinase 2 (TK2) Inhibitors and New Perspectives for Potential Applications
Volume: 18 Issue: 20
Author(s): Eva-Maria Priego, Anna Karlsson, Federico Gago, Maria-Jose Camarasa, Jan Balzarini and Maria-Jesus Perez-Perez
Affiliation:
Keywords: Mitochondrial thymidine kinase 2 (TK2), nucleoside metabolism, enzymatic inhibitors, mitochondrial depletion syndrome (MDS), tumorigenesis, chromosome 16q22, deoxynucleoside kinase (dNK), reverse transcriptase, cancer treatment, nucleoside analogues
Abstract: Thymidine kinase 2 (TK2), encoded on chromosome 16q22 of the human genome, is a deoxynucleoside kinase (dNK) that catalyzes the phosphorylation of the pyrimidine deoxynucleosides 2’-deoxythymidine (dThd), 2’-deoxyuridine (dUrd) and 2’- deoxycytidine (dCyd) to the corresponding deoxynucleoside 5’-monophosphate derivatives. In contrast to the S-phase-specific thymidine kinase 1 (TK1), TK2 is constitutively expressed in the mitochondria and plays an important role in providing dNTPs for the replication and maintenance of mitochondrial DNA (mtDNA). The severe mitochondrial DNA depletion syndrome (MDS) has been associated with mutations in TK2, resulting in mtDNA depletion, isolated skeletal myopathy, and death of the individual at an early stage of life. Some antiviral nucleoside analogs, such as 3’-azido-dThd (AZT) that is targeting the human immunodeficiency virus (HIV)-encoded reverse transcriptase, are substrates for TK2 and it has been proposed that the mitochondrial toxicity observed after prolonged treatment with such drugs could be due to their interaction with TK2. Therefore, the design of specific TK2 inhibitors may be useful to investigate the role of TK2 in the maintenance and homeostasis of mitochondrial dNTP pools and its contribution to the mitochondrial toxicity of several antiviral and anticancer drugs. Since 2000, several potent and selective TK2 inhibitors have been described. Besides bringing together previously reported inhibitors, special attention will be paid in this review to the new families of TK2 inhibitors more recently described, together with modeling studies and biological assays. Moreover, the last section will be focused on several recent investigations that suggest that depletion of mtDNA can take place both in tumorigenesis and during cancer treatment with certain nucleoside analogues.
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Cite this article as:
Priego Eva-Maria, Karlsson Anna, Gago Federico, Camarasa Maria-Jose, Balzarini Jan and Perez-Perez Maria-Jesus, Recent Advances in Thymidine Kinase 2 (TK2) Inhibitors and New Perspectives for Potential Applications, Current Pharmaceutical Design 2012; 18 (20) . https://dx.doi.org/10.2174/138161212800672787
DOI https://dx.doi.org/10.2174/138161212800672787 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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