title: Recent advances in thymidine kinase 2 (TK2) inhibitors and new perspectives for potential applications.
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.
authors.affiliation: Instituto de Química Médica (C.S.I.C.), C/Juan de la Cierva, 3, E-28006 Madrid, Spain. empriego@iqm.csic.es
authors.forename: Eva-María
authors.initials: EM
authors.lastname: Priego
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; C105339:thymidine kinase 2; D013937:Thymidine Kinase