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.
Export Options
About this article
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 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Cancer Stem Cells and their Management in Cancer Therapy
Recent Patents on Anti-Cancer Drug Discovery The Roles of Parathyroid Hormone and Calcitonin in Bone Remodeling: Prospects for Novel Therapeutics
Endocrine, Metabolic & Immune Disorders - Drug Targets The Vitamin D/CYP24A1 Story in Cancer
Anti-Cancer Agents in Medicinal Chemistry Anticancer Advances of Matrine and Its Derivatives
Current Pharmaceutical Design Characterization of β-Sitosterol for Potential Selective GR Modulation
Protein & Peptide Letters Targeted Radiotherapy of Bone Malignancies
Current Drug Discovery Technologies Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed
Current Drug Targets The Synthesis of Nano-Doxorubicin and its Anticancer Effect
Anti-Cancer Agents in Medicinal Chemistry Targeting Cancer Stem Cells with Repurposed Drugs to Improve Current Therapies
Recent Patents on Anti-Cancer Drug Discovery The Role of the Osteoimmune Axis in the Inflammation of the Inner Auditory Ear and with Regard to the Putative Anticarcinogenetic Principle: Part 2
Inflammation & Allergy - Drug Targets (Discontinued) Anabolics in Osteoporosis: The Emerging Therapeutic Tool
Current Molecular Medicine A Novel Lily-of-the-Valley Fragrance Contrast Agent for Magnetic Resonance and Fluorescence Imaging of Prostate Cancer Cells
Current Pharmaceutical Biotechnology Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets
Anti-Cancer Agents in Medicinal Chemistry HSP90 Inhibitors: Current Development and Potential in Cancer Therapy
Recent Patents on Anti-Cancer Drug Discovery A Novel Method for Screening of Anti-Cancer Drugs: Availability of Screening in Acidic Medium
Recent Patents on Biomedical Engineering (Discontinued) Neurokinin-1 Receptor Antagonists as Anticancer Drugs
Letters in Drug Design & Discovery Characterizing the Relationship Between the Chemical Structures of Drugs and their Activities on Primary Cultures of Pediatric Solid Tumors
Current Medicinal Chemistry Recent Progress in the Development of Natural ent-Kaurane Diterpenoids with Anti-tumor Activity
Mini-Reviews in Medicinal Chemistry Cell Penetrating Peptides for Tumor Targeting
Current Pharmaceutical Biotechnology Molecular Mechanisms of Thymoquinone as Anticancer Agent
Combinatorial Chemistry & High Throughput Screening