Abstract
The Hsp90 molecular chaperone has emerged as one of the most exciting targets for cancer drug development. Hsp90 is overexpressed in many malignancies, very likely as a result of the stress that is induced both by the hostile cancer microenvironment and also by the mutation and abberant expression of oncoproteins. A particularly attractive feature of Hsp90 as a cancer drug target is that it is required for the conformational stability and function of a wide range of oncogenic ‘client’ proteins, including c-Raf-1, Cdk4, ErbB2, mutant p53, c-Met, Polo-1 and telomerase hTERT. Inhibition of Hsp90 should therefore block multiple mission critical oncogenic pathways in the cancer cell, leading to inhibition of all the hallmark traits of malignancy. This combinatorial blockade of oncogenic targets should give rise to board spectrum antitumour activity across multiple cancer types. The ‘druggability’ of Hsp90 was confirmed by the discovery that the natural products geldanamycin and radicicol, which have anticancer activity, exert their biological effects by inhibiting the essential ATPase activity associated with the N-terminal domain of the protein. The first-inclass Hsp90 inhibitor has entered clinical trial and provided proof of concept that Hsp90 can be inhibited and clinical benefit seen at non-toxic doses. Further development is underway and a related analogue 17DMAG also shows promise in preclinical models. In addition, novel Hsp90 inhibitors have been identified using methods such as high throughput screening and x-ray crystallography. The opportunities and challenges involved in translating the fast moving biology of Hsp90 into patient benefit is discussed.
Keywords: chaperone, Hsp90 Drugs, crystallography, 17DMAG, N-terminal domain
Current Cancer Drug Targets
Title: Overview: Translating Hsp90 Biology into Hsp90 Drugs
Volume: 3 Issue: 5
Author(s): Paul Workman
Affiliation:
Keywords: chaperone, Hsp90 Drugs, crystallography, 17DMAG, N-terminal domain
Abstract: The Hsp90 molecular chaperone has emerged as one of the most exciting targets for cancer drug development. Hsp90 is overexpressed in many malignancies, very likely as a result of the stress that is induced both by the hostile cancer microenvironment and also by the mutation and abberant expression of oncoproteins. A particularly attractive feature of Hsp90 as a cancer drug target is that it is required for the conformational stability and function of a wide range of oncogenic ‘client’ proteins, including c-Raf-1, Cdk4, ErbB2, mutant p53, c-Met, Polo-1 and telomerase hTERT. Inhibition of Hsp90 should therefore block multiple mission critical oncogenic pathways in the cancer cell, leading to inhibition of all the hallmark traits of malignancy. This combinatorial blockade of oncogenic targets should give rise to board spectrum antitumour activity across multiple cancer types. The ‘druggability’ of Hsp90 was confirmed by the discovery that the natural products geldanamycin and radicicol, which have anticancer activity, exert their biological effects by inhibiting the essential ATPase activity associated with the N-terminal domain of the protein. The first-inclass Hsp90 inhibitor has entered clinical trial and provided proof of concept that Hsp90 can be inhibited and clinical benefit seen at non-toxic doses. Further development is underway and a related analogue 17DMAG also shows promise in preclinical models. In addition, novel Hsp90 inhibitors have been identified using methods such as high throughput screening and x-ray crystallography. The opportunities and challenges involved in translating the fast moving biology of Hsp90 into patient benefit is discussed.
Export Options
About this article
Cite this article as:
Workman Paul, Overview: Translating Hsp90 Biology into Hsp90 Drugs, Current Cancer Drug Targets 2003; 3 (5) . https://dx.doi.org/10.2174/1568009033481868
DOI https://dx.doi.org/10.2174/1568009033481868 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...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
Related Articles
-
KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions
Current Genomics Common and Uncommon Features of Rheumatoid Arthritis and Chronic Obstructive Pulmonary Disease: Clues to a Future Therapy
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Repositioning of DHFR Inhibitors
Current Topics in Medicinal Chemistry The Application of Single Nucleotide Polymorphism Microarrays in Cancer Research
Current Genomics Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
Current Pharmaceutical Design Regulatory Overview of Biosimilars: Current Scenario and Future Opportunities
Applied Clinical Research, Clinical Trials and Regulatory Affairs New Insight into P-Glycoprotein as a Drug Target
Anti-Cancer Agents in Medicinal Chemistry Lipid-Based Nanoparticulate Systems for the Delivery of Anti-Cancer Drug Cocktails: Implications on Pharmacokinetics and Drug Toxicities
Current Drug Metabolism The Role of Stress Proteins in Prostate Cancer
Current Genomics Tartrate-Resistant Acid Phosphatase: A Target for Anti-Osteoporotic Chemotherapeutics
Current Enzyme Inhibition MicroRNAs as Regulators in Normal Hematopoietic and Leukemia Stem Cells: Current Concepts and Clinical Implications
Current Molecular Medicine Role of the Bone Marrow Microenvironment in Drug Resistance of Hematological Malignances
Current Medicinal Chemistry Phytochemistry and Pharmacognosy of Naturally Occurring Prenyloxyanthraquinones
Current Drug Targets Anticancer Effects of Ginsenoside Rh2: A Systematic Review
Current Molecular Pharmacology Recent Advances in the Development of Selective Mcl-1 Inhibitors for the Treatment of Cancer (2017-Present)
Recent Patents on Anti-Cancer Drug Discovery Editorial [Hot Topic: Stem Cells and Tissue Regeneration (Executive Guest Editor: Roberta Di Pietro)]
Current Pharmaceutical Design Novel Targets for Apoptosis Modulation: BAG3 Protein and Other Co- Chaperones
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Recent Advances in Small Molecule Prodrugs for Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Insights into the Structural Features Essential for JAK2 Inhibition and Selectivity
Current Medicinal Chemistry Immunotherapy for Myeloproliferative Neoplasms (MPN)
Current Cancer Drug Targets