ivosidenib   Click here for help

GtoPdb Ligand ID: 9217

Synonyms: AG-120 | AG120 | Tibsovo®
Approved drug
ivosidenib is an approved drug (FDA (2018), EMA (2023))
Compound class: Synthetic organic
Comment: Ivosidenib (AG-120) is an orally active, selective inhibitor of isocitrate dehydrogenase 1 (IDH1) [5], in particular with activity against IDH1 R132H or R132C mutants. It is one of the compounds claimed in Agios' patent WO2013107291, where it is Compound 176 [4]. It is structurally related to AGI-5198 also from Agios.
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 9
Hydrogen bond donors 1
Rotatable bonds 9
Topological polar surface area 119.29
Molecular weight 582.14
XLogP 3.28
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES N#Cc1ccnc(c1)N1C(=O)CCC1C(=O)N(C(c1ccccc1Cl)C(=O)NC1CC(C1)(F)F)c1cncc(c1)F
Isomeric SMILES N#Cc1ccnc(c1)N1C(=O)CC[C@H]1C(=O)N([C@@H](c1ccccc1Cl)C(=O)NC1CC(C1)(F)F)c1cncc(c1)F
InChI InChI=1S/C28H22ClF3N6O3/c29-21-4-2-1-3-20(21)25(26(40)36-18-11-28(31,32)12-18)37(19-10-17(30)14-34-15-19)27(41)22-5-6-24(39)38(22)23-9-16(13-33)7-8-35-23/h1-4,7-10,14-15,18,22,25H,5-6,11-12H2,(H,36,40)/t22-,25-/m0/s1
InChI Key WIJZXSAJMHAVGX-DHLKQENFSA-N
No information available.
Summary of Clinical Use Click here for help
Ivosidenib (AG-120) was initially granted orphan drug designation by the US FDA for the treatment of acute myeloid leukemia (AML) in patients carrying IDH1 gene mutations. Full approval was granted in July 2018 for the treatment of relapsed/refractory IDH1-mutated AML, with approval based on results from clinical trial NCT02074839 [3]. Differentaition syndrome [1], QT prolongation and Guillain-Barré syndrome are serious adverse reactions that are highlighted in the Medication Guide provided to patients who are given this drug.

Clinical trials in various other IDH1-mutant positive hematologic malignancies and solid tumours (e.g. cholangiocarcinoma, chondrosarcoma and glioma) were continued. Click here to link to ClinicalTrials.gov's full list of AG-120 trials.
In May 2019 the FDA expanded ivosidenib's approval to include use as a treatment for newly-diagnosed IDH1-mutant AML in patients who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. In August 2021, the FDA approval was expanded again to include patients with previously treated, locally advanced or metastatic IDH1 mutation +ve cholangiocarcinoma.
In Europe the EMA granted ivosidenib orphan designation for the treatment of AML (2016) and biliary tract cancer (2018) with IDH1 mutations.
In May 2023, the EMA issued full approvals for use of ivosidenib for additional rare cancers; in combination with azacitidine to treat newly diagnosed IDH1R132 AML, and as monotherapy for previously treated locally advanced/metastatic IDH1R132 positive cholangiocarcinoma.
In October 2023, FDA approval was granted for ivosidenib's use as a treatment for relapsed/refractory myelodysplastic syndromes (MDS) with a susceptible IDH1 mutation.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Mutations of IDH1 (in particular mutation of Arg 132) present in certain cancer cells cause altered (and abnormal) enzymatic activity, permitting IDH1 to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer [2].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02074839 Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation Phase 1 Interventional Agios Pharmaceuticals, Inc.