Abstract
This manuscript describes the discovery and characterization of inhibitors of the lipid phosphatase SHIP2, an important target for the treatment of Type 2 diabetes, using the Automated Ligand Identification System. ALIS is an affinity selection-mass spectrometry platform for label-free, high throughput screening of mixture-based combinatorial libraries. We detail the mass-encoded synthesis of a library that yielded NGD-61338, a pyrazole-based SHIP2 inhibitor. Quantitative ALIS affinity measurements and inhibition of SHIP2 enzymatic activity indicate that this compound has micromolar binding affinity and inhibitory activity for this target. This inhibitor, which does not contain a phosphatase “warhead,” binds the active site of SHIP2 as determined by ALIS-based competition experiments with the enzymes natural substrate, phosphatidylinositol 3,4,5-triphosphate (PIP3). Structure-activity relationships for NGD-61338 and two other ligand classes discovered by ALIS screening were explored using a combination of combinatorial library synthesis and ALIS-enabled affinity ranking in compound mixtures.
Keywords: Affinity selection, mass spectrometry, high throughput screening, label-free, SHIP2, ALIS
Combinatorial Chemistry & High Throughput Screening
Title: Inhibitors of the Lipid Phosphatase SHIP2 Discovered by High Throughput Affinity Selection-Mass Spectrometry Screening of Combinatorial Libraries
Volume: 12 Issue: 8
Author(s): D. Allen Annis, Cliff C. Cheng, Cheng-Chi Chuang, John D. McCarter, Huw M. Nash, Naim Nazef, Todd Rowe, Robert J.M. Kurzeja and Gerald W. Shipps Jr.
Affiliation:
Keywords: Affinity selection, mass spectrometry, high throughput screening, label-free, SHIP2, ALIS
Abstract: This manuscript describes the discovery and characterization of inhibitors of the lipid phosphatase SHIP2, an important target for the treatment of Type 2 diabetes, using the Automated Ligand Identification System. ALIS is an affinity selection-mass spectrometry platform for label-free, high throughput screening of mixture-based combinatorial libraries. We detail the mass-encoded synthesis of a library that yielded NGD-61338, a pyrazole-based SHIP2 inhibitor. Quantitative ALIS affinity measurements and inhibition of SHIP2 enzymatic activity indicate that this compound has micromolar binding affinity and inhibitory activity for this target. This inhibitor, which does not contain a phosphatase “warhead,” binds the active site of SHIP2 as determined by ALIS-based competition experiments with the enzymes natural substrate, phosphatidylinositol 3,4,5-triphosphate (PIP3). Structure-activity relationships for NGD-61338 and two other ligand classes discovered by ALIS screening were explored using a combination of combinatorial library synthesis and ALIS-enabled affinity ranking in compound mixtures.
Export Options
About this article
Cite this article as:
Annis Allen D., Cheng C. Cliff, Chuang Cheng-Chi, McCarter D. John, Nash M. Huw, Nazef Naim, Rowe Todd, Kurzeja J.M. Robert and Shipps Jr. W. Gerald, Inhibitors of the Lipid Phosphatase SHIP2 Discovered by High Throughput Affinity Selection-Mass Spectrometry Screening of Combinatorial Libraries, Combinatorial Chemistry & High Throughput Screening 2009; 12 (8) . https://dx.doi.org/10.2174/138620709789104870
DOI https://dx.doi.org/10.2174/138620709789104870 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...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
-
A Comprehensive Review on Recent advances in Synthesis & Pharmacotherapeutic potential of Benzothiazoles
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Giardiasis: Recent Progress in Chemotherapy and Drug Development (Hot Topic: Anti-Infective Agents Executive Editors: Mitchell A. Avery / Vassil St.) Georgiev
Current Pharmaceutical Design Na+/Ca2+ Exchange Inhibitors: A New Class of Calcium Regulators
Cardiovascular & Hematological Disorders-Drug Targets Variation at Interleukin-10 Locus Represents Susceptibility to Psoriasis in North Indian Population
Endocrine, Metabolic & Immune Disorders - Drug Targets Antioxidant and Antinociceptive Activities of Methanol Extract of Muehlenbeckia sagittifolia
Current Traditional Medicine Can Exercise Minimize Postprandial Oxidative Stress in Patients with Type 2 Diabetes?
Current Diabetes Reviews Type 1 Diabetes and Physical Exercise: Moving (forward) as an Adjuvant Therapy
Current Pharmaceutical Design Visceral Fat as Target of Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome
Current Pharmaceutical Design Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Therapeutics: Rationales, Controversies, Clinical Experience
Current Drug Targets Energetic Metabolic Roles in Pulmonary Arterial Hypertension and Right Ventricular Remodeling
Current Pharmaceutical Design Effect of Dipeptidyl Peptidase-4 Inhibitors on Plasma Adiponectin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Current Medicinal Chemistry Renin-Angiotensin System in Diabetes
Protein & Peptide Letters Brain Targeted Drug Delivery: Factors, Approaches and Patents
Recent Patents on Nanomedicine Impact of Aging on the Angiogenic Potential of the Myocardium: Implications for Angiogenic Therapies with Emphasis on Sirtuin Agonists
Recent Patents on Cardiovascular Drug Discovery Blocking HIV-1 Vif Restores a Natural Mechanism of Intracellular Antiviral Defense
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Echinoderms: Potential Model Systems for Studies on Muscle Regeneration
Current Pharmaceutical Design The Pathophysiology of Uric Acid in Relation to Cardiovascular Disease
Current Cardiology Reviews Berberine: A Fluorescent Alkaloid with a Variety of Applications from Medicine to Chemistry
Mini-Reviews in Organic Chemistry Angiotensin II-Vasopressin Interactions in The Regulation of Cardiovascular Functions. Evidence for an Impaired Hormonal Sympathetic Reflex in Hypertension and Congestive Heart Failure
Endocrine, Metabolic & Immune Disorders - Drug Targets Large Artery Stiffness and Antihypertensive Agents
Current Pharmaceutical Design