Abstract
Most anticancer drugs presently used clinically target genomic DNA. The selectivity of these anticancer drugs for tumor tissues is probably due to tumor-specific defects suppressing cell cycle checkpoints and DNA repair, and enhancing apoptotic response in the tumor. We will review the molecular interactions within the ATM-Chk2 pathway implicating the DNA damage sensor kinases (ATM, ATR and DNA-PK), the adaptor BRCT proteins (Nbs1, Brca1, 53BP1, MDC1) and the effector kinases (Chk2, Chk1, Plk3, JNK, p38). The molecular interaction map convention (MIM) will be used for presenting this molecular network (http://discover.nci.nih.gov/mim/). A characteristic of the ATM-Chk2 pathway is its redundancy. First, ATM and Chk2 phosphorylate common substrates including p53, E2F1, BRCA1, and Chk2 itself, which suggests that Chk2 (also known as CHECK2, Cds1 in fission yeast, and Dmchk2 or Dmnk or Loki in the fruit fly) acts as a relay for ATM and/or as a salvage pathway when ATM is inactivated. Secondly, redundancy is apparent for the substrates, which can be phosphorylated/activated at similar residues by Chk2, Chk1, and the polo kinases (Plks). Functionally, Chk2 can activate both apoptosis (via p53, E2F1 and PML) and cell cycle checkpoint (via Cdc25A and Cdc25C, p53, and BRCA1). We will review the short list of published Chk2 inhibitors. We will also propose a novel paradigm for screening interfacial inhibitors of Chk2. Chk2 inhibitors might be used to enhance the tumor selectivity of DNA targeted agents in p53-deficient tumors, and for the treatment of tumors whose growth depends on enhanced Chk2 activity.
Keywords: cell cycle checkpoints, apoptosis, dna double-strand breaks, dna repair
Current Pharmaceutical Design
Title: Targeting Chk2 Kinase: Molecular Interaction Maps and Therapeutic Rationale
Volume: 11 Issue: 22
Author(s): Y. Pommier, O. Sordet, A. Rao, H. Zhang and K. W. Kohn
Affiliation:
Keywords: cell cycle checkpoints, apoptosis, dna double-strand breaks, dna repair
Abstract: Most anticancer drugs presently used clinically target genomic DNA. The selectivity of these anticancer drugs for tumor tissues is probably due to tumor-specific defects suppressing cell cycle checkpoints and DNA repair, and enhancing apoptotic response in the tumor. We will review the molecular interactions within the ATM-Chk2 pathway implicating the DNA damage sensor kinases (ATM, ATR and DNA-PK), the adaptor BRCT proteins (Nbs1, Brca1, 53BP1, MDC1) and the effector kinases (Chk2, Chk1, Plk3, JNK, p38). The molecular interaction map convention (MIM) will be used for presenting this molecular network (http://discover.nci.nih.gov/mim/). A characteristic of the ATM-Chk2 pathway is its redundancy. First, ATM and Chk2 phosphorylate common substrates including p53, E2F1, BRCA1, and Chk2 itself, which suggests that Chk2 (also known as CHECK2, Cds1 in fission yeast, and Dmchk2 or Dmnk or Loki in the fruit fly) acts as a relay for ATM and/or as a salvage pathway when ATM is inactivated. Secondly, redundancy is apparent for the substrates, which can be phosphorylated/activated at similar residues by Chk2, Chk1, and the polo kinases (Plks). Functionally, Chk2 can activate both apoptosis (via p53, E2F1 and PML) and cell cycle checkpoint (via Cdc25A and Cdc25C, p53, and BRCA1). We will review the short list of published Chk2 inhibitors. We will also propose a novel paradigm for screening interfacial inhibitors of Chk2. Chk2 inhibitors might be used to enhance the tumor selectivity of DNA targeted agents in p53-deficient tumors, and for the treatment of tumors whose growth depends on enhanced Chk2 activity.
Export Options
About this article
Cite this article as:
Pommier Y., Sordet O., Rao A., Zhang H. and Kohn W. K., Targeting Chk2 Kinase: Molecular Interaction Maps and Therapeutic Rationale, Current Pharmaceutical Design 2005; 11 (22) . https://dx.doi.org/10.2174/1381612054546716
DOI https://dx.doi.org/10.2174/1381612054546716 |
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
-
Blockade of Insulin-Like Growth Factor Type-1 Receptor with Cixutumumab (IMC-A12): A Novel Approach to Treatment for Multiple Cancers
Current Drug Targets Novel Biomarkers for Risk Stratification and Identification of Lifethreatening Cardiovascular Disease: Troponin and Beyond
Current Cardiology Reviews The Relationship Between Inflammation, Platelet Activation and Antiplatelet Resistance
Inflammation & Allergy - Drug Targets (Discontinued) Cancer Chemoprevention by Targeting the Epigenome
Current Drug Targets Molecular Mechanisms of Inherited Arrhythmias
Current Genomics Regulation of HIV-1 Transcription by Protein Phosphatase 1
Current HIV Research CPR Education
Current Pediatric Reviews The Tree of Sirtuins and the Garden of Cardiovascular Youth
Current Vascular Pharmacology Pharmacotherapy of Mixed Dyslipidemia in the Metabolic Syndrome
Current Clinical Pharmacology Pharmacotherapeutic Approach to Prevent or Treat Chronic Allograft Nephropathy
Current Drug Targets - Cardiovascular & Hematological Disorders Ghrelin and Growth Hormone Secretagogues, Physiological and Pharmacological Aspect
Current Drug Discovery Technologies Aging and Remodeling During Healing of the Wounded Heart: Current Therapies and Novel Drug Targets
Current Drug Targets Targeted Regulation of PI3K/Akt/mTOR/NF-κB Signaling by Indole Compounds and their Derivatives: Mechanistic Details and Biological Implications for Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry The GLUTs Family - Lessons from Transgenic Mice
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Effect of Mineralocorticoid Receptor Antagonists in Heart Failure with Preserved Ejection Fraction and with Reduced Ejection Fraction - A Narrative Review
Current Vascular Pharmacology Long-Term Use of Short- and Long-Acting Nitrates in Stable Angina Pectoris
Current Clinical Pharmacology Cardioprotective Potential of Iron Chelators and Prochelators
Current Medicinal Chemistry Insect Peptides – Perspectives in Human Diseases Treatment
Current Medicinal Chemistry Pleiotropic Effects of Omega-3 Fatty Acids
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Defective Insulin Signalling, Mediated by Inflammation, Connects Obesity to Alzheimer Disease; Relevant Pharmacological Therapies and Preventive Dietary Interventions
Current Alzheimer Research