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Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Novartis Inst. for BioMedical Research, Cambridge, MA (United States)
+ Show Author Affiliations
Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. We report preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
OSTI ID:
1515280
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 10 Vol. 8; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (25)

Systematic Evaluation of Wajima Superposition (Steady-State Concentration to Mean Residence Time) in the Estimation of Human Intravenous Pharmacokinetic Profile journal March 2016
Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity journal March 2017
Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1 journal January 2017
Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity journal October 2014
Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo journal August 2012
Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase journal May 2013
Direct and Convenient Conversion of Alcohols to Fluorides journal April 2004
Fit-for-Purpose Development of the Enabling Route to Crizotinib (PF-02341066) journal September 2011
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate journal November 2009
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia journal November 2011
Reductive carboxylation supports growth in tumour cells with defective mitochondria journal November 2011
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia journal October 2015
High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response journal October 2015
Cancer-associated IDH mutations: biomarker and therapeutic opportunities journal October 2010
IDH1 and IDH2 Mutations in Gliomas journal February 2009
Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of  -ketoglutarate to citrate to support cell growth and viability journal November 2011
Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule journal November 2014
Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism journal May 2010
An Integrated Genomic Analysis of Human Glioblastoma Multiforme journal September 2008
An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells journal April 2013
Abstract PL04-05: The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a Phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas
  • Burris, Howard; Mellinghoff, Ingo; Maher, Elizabeth
  • Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA, Clinical Trials https://doi.org/10.1158/1535-7163.TARG-15-PL04-05
conference January 2016
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities journal June 2013
Identification and Characterization of Small-Molecule Inhibitors of the R132H/R132H Mutant Isocitrate Dehydrogenase 1 Homodimer and R132H/Wild-Type Heterodimer journal September 2014
Longitudinal Pharmacokinetic/Pharmacodynamic Profile of AG-120, a Potent Inhibitor of the IDH1 Mutant Protein, in a Phase 1 Study of IDH1-Mutant Advanced Hematologic Malignancies journal December 2015
IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication journal August 2010

Cited By (12)

Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers journal January 2018
Isocitrate dehydrogenase inhibitors in acute myeloid leukemia journal October 2019
Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer journal June 2018
Metabolic Plasticity in Chemotherapy Resistance journal March 2020
Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies journal February 2018
Genetic Abnormalities, Clonal Evolution, and Cancer Stem Cells of Brain Tumors journal October 2018
One‐Step Synthesis of 3,4‐Disubstituted 2‐Oxazolidinones by Base‐Catalyzed CO 2 Fixation and Aza‐Michael Addition journal July 2019
The clinical use of IDH1 and IDH2 mutations in gliomas journal November 2018
An olive oil phenolic is a new chemotype of mutant isocitrate dehydrogenase 1 (IDH1) inhibitors journal November 2018
Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease journal May 2019
Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics journal May 2019
Approaches to PET Imaging of Glioblastoma journal January 2020

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Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity
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Related Subjects

60 APPLIED LIFE SCIENCES
Mutant IDH1
brain penetration
clinical candidate
in vivo anticancer activity
inhibition of 2-HG production