Abstract
Isocitrate dehydrogenase (IDH) is a metabolic enzyme that converts isocitrate to α-ketoglutarate (α-KG). Genetic gain-of-function mutations in IDH1 and IDH2 confer a neomorphic activity that allow reduction of α -KG to (R)-2- hydroxyglutarate, the accumulation of which results in the development of cancers like low grade gliomas and leukemia. After treatment with AG-221 in clinical trials, a first-in-class inhibitor of mutated IDH2, 29 patients with acute myeloid leukemia or myelodysplastic syndrome experience complete remissions and the overall response rate is 59/159 (37%). Thus, IDH mutants have become intriguing targets for cancer therapeutics. In addition to providing a brief summary of IDH mutations, this review describes known inhibitors with potential activities against IDH mutants such as AG-120, AG-221, AG-881 and AGI-6780. The evolving landscape of IDH mutant inhibitors provides us an outlook on the discovery of novel, safer, and more effective cancer treatment strategies.
Keywords: Cancer, drug discovery, IDH1, IDH2, inhibitor, mutant.
Mini-Reviews in Medicinal Chemistry
Title:The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors
Volume: 16 Issue: 16
Author(s): Jiao Chen, Jie Yang and Peng Cao
Affiliation:
Keywords: Cancer, drug discovery, IDH1, IDH2, inhibitor, mutant.
Abstract: Isocitrate dehydrogenase (IDH) is a metabolic enzyme that converts isocitrate to α-ketoglutarate (α-KG). Genetic gain-of-function mutations in IDH1 and IDH2 confer a neomorphic activity that allow reduction of α -KG to (R)-2- hydroxyglutarate, the accumulation of which results in the development of cancers like low grade gliomas and leukemia. After treatment with AG-221 in clinical trials, a first-in-class inhibitor of mutated IDH2, 29 patients with acute myeloid leukemia or myelodysplastic syndrome experience complete remissions and the overall response rate is 59/159 (37%). Thus, IDH mutants have become intriguing targets for cancer therapeutics. In addition to providing a brief summary of IDH mutations, this review describes known inhibitors with potential activities against IDH mutants such as AG-120, AG-221, AG-881 and AGI-6780. The evolving landscape of IDH mutant inhibitors provides us an outlook on the discovery of novel, safer, and more effective cancer treatment strategies.
Export Options
About this article
Cite this article as:
Chen Jiao, Yang Jie and Cao Peng, The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors, Mini-Reviews in Medicinal Chemistry 2016; 16 (16) . https://dx.doi.org/10.2174/1389557516666160609085520
DOI https://dx.doi.org/10.2174/1389557516666160609085520 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer?s, Parkinson?s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...read more
Natural Products in Drug Discovery
Natural products have always been one of the important ways of drug discovery due to their novel skeleton and diverse functional group characteristics. According to statistics, between 1981 and 2019, the FDA approved a total of 1,394 small molecule drugs for marketing, of which 930 marketed drugs originated from 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
-
Role of Prolyl Endopeptidase in Intracellular Transport and Protein Secretion
CNS & Neurological Disorders - Drug Targets Medicinal Chemistry of Drugs with Active Metabolites Following Conjugation
Mini-Reviews in Medicinal Chemistry Meet Our Editorial Board Member
Current Medicinal Chemistry Glioblastoma Tumor Initiating Cells: Therapeutic Strategies Targeting Apoptosis and MicroRNA Pathways
Current Molecular Medicine Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety
Anti-Cancer Agents in Medicinal Chemistry Neuropeptide-Derived Antimicrobial Peptides from Invertebrates for Biomedical Applications
Current Medicinal Chemistry Cellular Uptake and Organ Accumulation of Amphipolar Metallocorroles with Cytoprotective and Cytotoxic Properties
Anti-Cancer Agents in Medicinal Chemistry Epigenetics: Relations to Disease and Laboratory Findings
Current Medicinal Chemistry Endogenous Regulators of Adult CNS Neurogenesis
Current Pharmaceutical Design Therapeutic Potential of Resveratrol in the Treatment of Glioma: Insights into its Regulatory Mechanisms
Mini-Reviews in Medicinal Chemistry Oncolytic Coxsackievirus and the Mechanisms of its Effects on Cancer: A Narrative Review
Current Cancer Therapy Reviews Anti-tumor Therapeutic Molecules that Target the Programmed Cell Death Machinery
Mini-Reviews in Medicinal Chemistry An Integrative Systems Analysis of High-grade Glioma Cell Lines: TLRs, Wnt, BRCA1, Netrins, STXBP1 and MDH1 Provide Putative Molecular Targets for Therapeutic Intervention
Current Pharmacogenomics and Personalized Medicine Hydrophobic Modification of Copper Nanospheres for Incorporation into Poloxamer Micelles, Aggregated Micellar Nanocages and Supramolecular Assemblies
Current Nanomedicine A Progressive Review of V600E-B-RAF-Dependent Melanoma and Drugs Inhibiting It
Mini-Reviews in Medicinal Chemistry Editorial (Thematic Issue: Microglia - A Therapeutic Target in Neurological Diseases and Disorders)
CNS & Neurological Disorders - Drug Targets Arsenic Trioxide Targets miR-125b in Glioma Cells
Current Pharmaceutical Design Applications of Nanosystems to Anticancer Drug Therapy (Part I. Nanogels, Nanospheres, Nanocapsules)
Recent Patents on Anti-Cancer Drug Discovery Aptamers: Selection, Modification and Application to Nervous System Diseases
Current Medicinal Chemistry Nasal Polyposis: An Overview of Differential Diagnosis and Treatment
Recent Patents on Inflammation & Allergy Drug Discovery