Abstract
In recent years, pharmaceutical companies have increasingly focused on phosphoinositide 3-kinases delta (PI3Kδ) and gamma (PI3Kγ) as therapeutic targets for the treatment of inflammatory and autoimmune diseases. All class 1 PI3-kinases (α/β/γ/δ) generate phospholipid second messengers that help govern cellular processes such as migration, proliferation, and apoptosis. PI3K δ/γ lipid kinases are mainly restricted to the hematopoetic system whereas PI3Kα/β are ubiquitously expressed, thus raising potential toxicity concerns for chronic indications such as asthma and rheumatoid arthritis. Therefore, the challenge in developing a small molecule inhibitor of PI3K is to define and attain the appropriate isoform selectivity profile. Significant advances in the design of such compounds have been achieved by utilizing x-ray crystal structures of various inhibitors bound to PI3Kγ in conjunction with pharmacophore modeling and high-throughput screening. Herein, we review the history and challenges involved with the discovery of small molecule isoform-specific PI3K inhibitors. Recent progress in the design of selective PI3Kδ, PI3Kγ, and PI3Kδ/γ dual inhibitors will be presented.
Keywords: PI3K, inflammation, allergy, asthma, rheumatoid arthritis, COPD
Current Topics in Medicinal Chemistry
Title: Small Molecule Inhibitors of Phosphoinositide 3-Kinase (PI3K) δ and γ
Volume: 9 Issue: 8
Author(s): Michael K. Ameriks and Jennifer D. Venable
Affiliation:
Keywords: PI3K, inflammation, allergy, asthma, rheumatoid arthritis, COPD
Abstract: In recent years, pharmaceutical companies have increasingly focused on phosphoinositide 3-kinases delta (PI3Kδ) and gamma (PI3Kγ) as therapeutic targets for the treatment of inflammatory and autoimmune diseases. All class 1 PI3-kinases (α/β/γ/δ) generate phospholipid second messengers that help govern cellular processes such as migration, proliferation, and apoptosis. PI3K δ/γ lipid kinases are mainly restricted to the hematopoetic system whereas PI3Kα/β are ubiquitously expressed, thus raising potential toxicity concerns for chronic indications such as asthma and rheumatoid arthritis. Therefore, the challenge in developing a small molecule inhibitor of PI3K is to define and attain the appropriate isoform selectivity profile. Significant advances in the design of such compounds have been achieved by utilizing x-ray crystal structures of various inhibitors bound to PI3Kγ in conjunction with pharmacophore modeling and high-throughput screening. Herein, we review the history and challenges involved with the discovery of small molecule isoform-specific PI3K inhibitors. Recent progress in the design of selective PI3Kδ, PI3Kγ, and PI3Kδ/γ dual inhibitors will be presented.
Export Options
About this article
Cite this article as:
Ameriks K. Michael and Venable D. Jennifer, Small Molecule Inhibitors of Phosphoinositide 3-Kinase (PI3K) δ and γ, Current Topics in Medicinal Chemistry 2009; 9 (8) . https://dx.doi.org/10.2174/156802609789044434
DOI https://dx.doi.org/10.2174/156802609789044434 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...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
-
Global Gastrointestinal Safety Profile of Etoricoxib and Lumiracoxib
Current Pharmaceutical Design Risk Factors for Myocardial Infarction in Women and Men: A Review of the Current Literature
Current Pharmaceutical Design Drug Repositioning: A Smart Approach for Combating SARS-CoV-2
Anti-Infective Agents Computational Drug Repositioning: A Lateral Approach to Traditional Drug Discovery?
Current Topics in Medicinal Chemistry Small Molecule Immunosuppressive Agents in Experimental and Clinical Transplantation
Current Drug Targets - Cardiovascular & Hematological Disorders Review of Patents for Microneedle Application Devices Allowing Fluid Injections Through the Skin
Recent Patents on Drug Delivery & Formulation Psoriatic Arthritis and Risk of Vertebral Fracture: A Systematic Review and Meta-Analysis
Current Rheumatology Reviews Novel MK2 Inhibitors by Fragment Screening
Combinatorial Chemistry & High Throughput Screening Anti-Arthritic Effects of Immunomodulatory Peptide Injected in Joints
Current Drug Delivery Novel Carriers for Controlled Site Specific Delivery of Anti-Inflammatory Agents
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Functional Genomics- and Network-driven Systems Biology Approaches for Pharmacogenomics and Toxicogenomics
Current Drug Metabolism The Molecular Organization of Polymers of Cartilage in Health and Disease
Current Organic Chemistry Sonoanatomy and Sonopathology of Complex Anatomic Areas
Current Rheumatology Reviews Selection of Healthy Volunteers According to their Multidrug Resistance Protein 1 Activity Does Not Affect Bioavailability of Quetiapine
Current Psychopharmacology Potential Role of IL-18 in the Immunopathogenesis of AIDS, HIVAssociated Lipodystrophy and Related Clinical Conditions
Current HIV Research Origin and Biological Significance of Shed-Membrane Microparticles
Endocrine, Metabolic & Immune Disorders - Drug Targets Current and Future Clinical Strategies in Colon Cancer Prevention and the Emerging Role of Chemoprevention
Current Pharmaceutical Design Recent Advances in the Development of Anti-Infective Prophylactic and/or Therapeutic Agents Based on Toll-Like Receptor (TLRs)
Recent Patents on Anti-Infective Drug Discovery The Role of Nuclear Factor-κB in Inflammatory Lung Disease
Inflammation & Allergy - Drug Targets (Discontinued) Use of Etanercept in the Treatment of Psoriasis and Psoriatic Arthritis
Reviews on Recent Clinical Trials