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Title

Recent Advances in Thymidine Kinase 2 (TK2) Inhibitors and New Perspectives for Potential Applications

AuthorsPriego, Eva María ; Karlsson, Anna; Gago, Federico ; Camarasa Rius, María José ; Balzarini, Jan; Peréz-Pérez, María-Jesús
KeywordsMitochondrial thymidine kinase 2 (TK2)
nucleoside metabolism
enzymatic inhibitors
mitochondrial depletion syndrome (MDS)
tumorigenesis
chromosome 16q22
deoxynucleoside kinase (dNK)
reverse transcriptase
cancer treatment
nucleoside analogues
Issue Date2012
PublisherBentham Science Publishers
CitationCurrent Pharmaceutical Design 18 (20) : 2981-2994 (2012)
AbstractThymidine 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.
Publisher version (URL)http://dx.doi.org/10.2174/138161212800672787
URIhttp://hdl.handle.net/10261/78192
DOI10.2174/138161212800672787
ISSN1381-6128
E-ISSN1873-4286
Appears in Collections:(IQM) Artículos
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