Abstract
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH1 and IDH2 regulate several cellular processes, including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumors, including gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and IDH2 mutations involve a gain in neomorphic activity that catalyzes αKG conversion to (R)-2- hydroxyglutarate ((R)-2HG). IDH mutation-mediated accumulation of (R)-2HG results in epigenetic dysregulation, altered gene expression, and a block in cellular differentiation. Targeting mutant IDH by development of small molecule inhibitors is a rapidly emerging therapeutic approach as evidenced by the recent approval of the first selective mutant IDH2 inhibitor AG-221 (enasidenib) for the treatment of IDH2-mutated AML. This review will focus on mutant isocitrate dehydrogenase as a therapeutic drug target and provides an update on selective and pan-mutant IDH1/2 inhibitors in clinical trials and other mutant IDH inhibitors that are under development.
Keywords: Isocitrate dehydrogenase, mutation, Glioma, AML, cancer metabolism, mIDH inhibitors, cancer.
Current Topics in Medicinal Chemistry
Title:Development of Novel Therapeutics Targeting Isocitrate Dehydrogenase Mutations in Cancer
Volume: 18 Issue: 6
Author(s): Horrick Sharma*
Affiliation:
- Department of Pharmaceutical Sciences, College of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK 73096,United States
Keywords: Isocitrate dehydrogenase, mutation, Glioma, AML, cancer metabolism, mIDH inhibitors, cancer.
Abstract: Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH1 and IDH2 regulate several cellular processes, including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumors, including gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and IDH2 mutations involve a gain in neomorphic activity that catalyzes αKG conversion to (R)-2- hydroxyglutarate ((R)-2HG). IDH mutation-mediated accumulation of (R)-2HG results in epigenetic dysregulation, altered gene expression, and a block in cellular differentiation. Targeting mutant IDH by development of small molecule inhibitors is a rapidly emerging therapeutic approach as evidenced by the recent approval of the first selective mutant IDH2 inhibitor AG-221 (enasidenib) for the treatment of IDH2-mutated AML. This review will focus on mutant isocitrate dehydrogenase as a therapeutic drug target and provides an update on selective and pan-mutant IDH1/2 inhibitors in clinical trials and other mutant IDH inhibitors that are under development.
Export Options
About this article
Cite this article as:
Sharma Horrick*, Development of Novel Therapeutics Targeting Isocitrate Dehydrogenase Mutations in Cancer, Current Topics in Medicinal Chemistry 2018; 18 (6) . https://dx.doi.org/10.2174/1568026618666180518091144
DOI https://dx.doi.org/10.2174/1568026618666180518091144 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
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
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Prognostic and Predictive Biomarkers in Cancer
Current Cancer Drug Targets Current State of ERG as Biomarker in Prostatic Adenocarcinoma
Current Cancer Drug Targets Can we Consider Zoledronic Acid a New Antitumor Agent? Recent Evidence in Clinical Setting
Current Cancer Drug Targets Radiolabeled Imaging Probes Targeting Angiogenesis for Personalized Medicine
Current Pharmaceutical Design Cyclopamine, a Naturally Occurring Alkaloid, and Its Analogues May Find Wide Applications in Cancer Therapy
Current Topics in Medicinal Chemistry Anticancer Properties of Flavonoids: Roles in Various Stages of Carcinogenesis
Cardiovascular & Hematological Agents in Medicinal Chemistry MicroRNAs in the Intracellular Space, Regulation of Organelle Specific Pathways in Health and Disease
MicroRNA miRNAs in Bone Development
Current Genomics Detection of Early Cancer: Genetics or Immunology? Serum Autoantibody Profiles as Markers of Malignancy
Anti-Cancer Agents in Medicinal Chemistry Glucocorticoids Pharmacology: Past, Present and Future
Current Pharmaceutical Design Histone Deacetylase Inhibitors: Recent Insights from Basic to Clinical Knowledge & Patenting of Anti-Cancer Actions
Recent Patents on Anti-Cancer Drug Discovery Dexamethasone Reduces Cell Adhesion and Migration of T47D Breast Cancer Cell Line
Anti-Cancer Agents in Medicinal Chemistry Targeted Therapies in Bone Sarcomas
Current Cancer Drug Targets CXCR4 and Glioblastoma
Anti-Cancer Agents in Medicinal Chemistry Novel Benzo[B]Furans with Anti-Microtubule Activity Upregulate Expression of Apoptotic Genes and Arrest Leukemia Cells in G2/M Phase
Anti-Cancer Agents in Medicinal Chemistry One Hundred Faces of Cyclopamine
Current Pharmaceutical Design Heparin, Heparan Sulfate and Heparanase in Cancer: Remedy for Metastasis?
Anti-Cancer Agents in Medicinal Chemistry The Current and Future Therapies for Human Osteosarcoma
Current Cancer Therapy Reviews Potential Association Between TLR4 and Chitinase 3-Like 1 (CHI3L1/YKL-40) Signaling on Colonic Epithelial Cells in Inflammatory Bowel Disease and Colitis-Associated Cancer
Current Molecular Medicine The Urokinase-type Plasminogen Activator and the Generation of Inhibitors of Urokinase Activity and Signaling
Current Pharmaceutical Design