Abstract
The approach of chemical genetics has been widely used to study biological systems and to discover new drugs, signaling pathways and targets. The current review focuses on the development and utilization of a cell- and caspase-based apoptosis induction assay for the discovery of apoptosis inducers. We began with the development of a cell based phenotypic assay, which was used for the identification of small molecules that exhibit apoptosis inducing activities, including N-phenyl nicotinamides, gambogic acid, indole-2-carboxylic acid benzylidene-hydrazides, 4-aryl-4H-chromenes and 3-aryl-5-aryl-1,2,4-oxadiazoles. Through medicinal chemistry and biological studies, in vivo active compounds were identified, such as MX116407 as a tumor vascular disrupting agent with potent in vivo anticancer activity. The molecular targets of in vivo active compounds were identified using reagents designed and synthesized based on the SAR, including the identification of tail-interacting protein 47 (TIP47), an insulin-like growth factor II (IGF II) receptor binding protein, as the molecular target of 3-aryl-5-aryl-1,2,4-oxadiazoles; and Transferrin receptor I (TfR), a transmembrane protein that interacts with transferrin (Tf) for the transport of iron into cells, as the molecular target of gambogic acid. We demonstrated that chemical genetics is a very useful approach for anticancer drug research, from the discovery of potential drugs, to the understanding of signaling pathways and identification of druggable targets.
Keywords: Chemical genetics, apoptosis inducers, HTS assay, target identification and validation, anticancer drug, SAR studies, tubulin inhibitors, transferrin receptors
Current Medicinal Chemistry
Title: A Chemical Genetics Approach for the Discovery of Apoptosis Inducers:From Phenotypic Cell Based HTS Assay and Structure-Activity Relationship Studies, to Identification of Potential Anticancer Agents and Molecular Targets.
Volume: 13 Issue: 22
Author(s): Cai Sui Xiong, John Drewe and Shailaja Kasibhatla
Affiliation:
Keywords: Chemical genetics, apoptosis inducers, HTS assay, target identification and validation, anticancer drug, SAR studies, tubulin inhibitors, transferrin receptors
Abstract: The approach of chemical genetics has been widely used to study biological systems and to discover new drugs, signaling pathways and targets. The current review focuses on the development and utilization of a cell- and caspase-based apoptosis induction assay for the discovery of apoptosis inducers. We began with the development of a cell based phenotypic assay, which was used for the identification of small molecules that exhibit apoptosis inducing activities, including N-phenyl nicotinamides, gambogic acid, indole-2-carboxylic acid benzylidene-hydrazides, 4-aryl-4H-chromenes and 3-aryl-5-aryl-1,2,4-oxadiazoles. Through medicinal chemistry and biological studies, in vivo active compounds were identified, such as MX116407 as a tumor vascular disrupting agent with potent in vivo anticancer activity. The molecular targets of in vivo active compounds were identified using reagents designed and synthesized based on the SAR, including the identification of tail-interacting protein 47 (TIP47), an insulin-like growth factor II (IGF II) receptor binding protein, as the molecular target of 3-aryl-5-aryl-1,2,4-oxadiazoles; and Transferrin receptor I (TfR), a transmembrane protein that interacts with transferrin (Tf) for the transport of iron into cells, as the molecular target of gambogic acid. We demonstrated that chemical genetics is a very useful approach for anticancer drug research, from the discovery of potential drugs, to the understanding of signaling pathways and identification of druggable targets.
Export Options
About this article
Cite this article as:
Sui Xiong Cai, Drewe John and Kasibhatla Shailaja, A Chemical Genetics Approach for the Discovery of Apoptosis Inducers:From Phenotypic Cell Based HTS Assay and Structure-Activity Relationship Studies, to Identification of Potential Anticancer Agents and Molecular Targets., Current Medicinal Chemistry 2006; 13 (22) . https://dx.doi.org/10.2174/092986706778201521
DOI https://dx.doi.org/10.2174/092986706778201521 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
Functional Genomics of Cardioprotection by Ischemic Conditioning and the Influence of Comorbid Conditions: Implications in Target Identification
Current Drug Targets Infrared-Spectroscopy: A Non-Invasive Tool for Medical Diagnostics and Drug Analysis
Current Medicinal Chemistry Proprotein Convertase Inhibitory Activities of Flavonoids Isolated from Oroxylum Indicum
Current Medicinal Chemistry Nutritional Antioxidants and Their Applications in Cardiometabolic Diseases
Infectious Disorders - Drug Targets Nearly Half of Uncontrolled Hypertensive Patients could be Controlled by High-dose Titration of Amlodipine in the Clinical Setting: The ACHIEVE Study
Current Hypertension Reviews Recent Advances in the Treatment of Neurogenic Erectile Dysfunction
Recent Patents on CNS Drug Discovery (Discontinued) Evaluation of Mucin as a Release Enhancer for Rectal Delivery of Glibenclamide
Current Drug Delivery Editorial [Hot Topic: Current Hypertension Reviews: Hot Topics Hypertension and Diabetes: An Emphasis on the RAS (Guest Editors: Karin A.M. Jandeleit-Dahm and Terri J. Allen)]
Current Hypertension Reviews Cardiovascular Effects of Omega-3 Free Fatty Acids.
Current Vascular Pharmacology Targeting Microglial Activation in Stroke Therapy: Pharmacological Tools and Gender Effects
Current Medicinal Chemistry Xanthan Gum and Its Derivatives as a Potential Bio-polymeric Carrier for Drug Delivery System
Current Drug Delivery Targeting NPY, CRF/UCNs and NPS Neuropeptide Systems to Treat Alcohol Use Disorder (AUD)
Current Medicinal Chemistry Determination of Lipoic Acid in the form of 2-S-pyridinium Derivative by High-performance Liquid Chromatography with Ultraviolet Detection
Current Analytical Chemistry Extracellular Hsp70: Export and Function
Current Protein & Peptide Science The Clinical Genetics of Psoriasis
Current Genomics Quantitative Ultrasound in Diagnosis of Metabolic Bone Diseases
Current Medical Imaging Assessment of Possible Drug Interactions in Patients with Psoriasis and Associated Comorbid Medical Conditions: An Observational Study
Reviews on Recent Clinical Trials Editorial (Hot Topic: Synthetic, Natural and Related Compounds: New Approach to Chronic Diseases Studies)
Current Topics in Medicinal Chemistry Beyond the Synapse and Hebb's Rule: Is the Rest of the Neuron More Important for Psychiatric Disorders?
Current Psychiatry Reviews Human Ether-a-Go-Go-Related Gene Channel Blockers and its Structural Analysis for Drug Design
Current Drug Targets