General
Preferred name
ivosidenib
Synonyms
AG-120 ()
AG-881 ()
Ivosidenib (AG-120) ()
IvosidenibAG-120A-1323AG120 ()
Tibsovo ()
P&D ID
PD046740
CAS
1448347-49-6
Tags
available
drug
Approved by
EMA
FDA
First approval
2018
Drug indication
Acute myeloid leukaemia
Haematological malignancy
Acute myeloid leukemia
Cholangiocarcinoma
Drug Status
approved
investigational
Max Phase
4.0
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
DESCRIPTION
Ivosidenib (AG-120) is an orally active, selective inhibitor of isocitrate dehydrogenase 1 (IDH1) , in particular with activity against IDH1 R132H or R132C mutants. It is being investigated for its anti-cancer actions against solid and liquid tumours. It is one of the compounds claimed in patent WO2013107291, where it is Compound 176 and is related to also from Agios.
ROE
Following oral administration, 77% of Ivosidenib is eliminated in the feces with 67% present as the parent drug [FDA Label]. 17% is excreted in the urine with 10% as the parent drug.; ; No clinically meaningful effects on elimination have been observed with mild to moderate renal impairment or mild hepatic impairment [FDA Label]. Changes in patients with severe renal impairment or moderate too severe hepatic impairment have not been investigated.
TOXICITY
Ivosidenib does not appear to be mutagenic or clastogenic [FDA Label]. In rats, uterine atrophy was noted as non-tolerated dose levels in a 90 day repeat dose test with twice daily adiminstration. Carcinogenicity has not been assessed.; ; Animal embryo-fetal tests suggest Ivosidenib may cause fetal harm in pregnant patients [FDA Label]. When administered to pregnant rabbits, embryo-fetal mortality and growth changes occurred starting doses equivalent to 2 times normal recommended human exposure.; ; Ivosidenib is associated with development of differentiation syndrome presenting as noninfectious leukocytosis [FDA Label], peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and increased serum creatinine. 19% of patients in a clinical trial experienced this.; ; Ivosidenib is also associated with QTc prolongation [FDA Label]. 9% of patients in a clinical trial were found to have a QTc interval greater than 500 msec and 14% had an increase from baseline greater than 60 msec.; ; Gullain-Barre syndrome is a rare but severe condition associated with Ivosidenib use [FDA Label]. <1% of patients in a clinical trial experienced this, presenting as motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing.
ABSORPTION
Ivosidenib has a Tmax of 3 hours following oral administration of a 2 250 mg tablets (total 500 mg) [FDA Label]. When given with a high-fat meal, Cmax increases by 98% and AUC by 25%.; ; The AUC and Cmax increase in a less than dose-proportional manner in the range of 200-1200 mg daily [FDA Label]. Accumulation ratios have been determined to be 1.9 for AUC and 1.5 for Cmax over the course of one month. Steady state is known to be reached within 14 days of daily administration.
DESCRIPTION
Ivosidenib (AG-120) is an orally active, selective inhibitor of isocitrate dehydrogenase 1 (IDH1), in particular with activity against IDH1 R132H or R132C mutants. It is being investigated for its anti-cancer actions against solid and liquid tumours. It is one of the compounds claimed in patent WO2013107291, where it is Compound 176 and is related to AGI-5198 also from Agios.
PHARMACODYNAMICS
Many cancers undergo missense mutations of their IDH1 gene leading to substitution of arginine 132 residue of the IDH1 enzyme [A35629. This substitution leads to reduced production of the normal carboxylic acid cycle metabolite α-ketoglutarate (α-KG) in favor of a new metabolite, D-2-hydroxyglutarate (D-2HG) which reaches levels of 50-100 fold that of wild type cells. D-2HG is a weak competitor to α-KG, inhibiting aKG-dependent dioxygenases, and is present . These dioxygenases include several histone demethylases. This leads to hypermethylation of histones, a dominant feature of AML, which is associated with less expression of cell-differentiation genes [A35631]. Furthermore, methylation sensitive insulators can no longer regulate the activation of oncogenes when histones are hypermethylated [A35630]. In AML this hypermethylation is known to disrupt hematopoietic differentiation [A35632].; ; Ivosidenib reduces the production of D-2HG, relieving the inhibition of histone demethylases and restoring normal methylation conditions [A35634]. This restores cell differentiation and oncogene regulation leading to regression of the cancer.
DESCRIPTION
Ivosidenib (AG-120) is an orally active inhibitor of isocitrate dehydrogenase 1 mutant (mIDH1) enzyme, it exhibits profound d-2-hydroxyglutatrate (2-HG) lowering in vivo. Ivosidenib (AG-120) has the potential for AML therapy due to its acceptable safety profile and clinical activity[1].
PRICE
131
DESCRIPTION
Ivosidenib (AG-120) is an orally active, selective inhibitor of isocitrate dehydrogenase 1 (IDH1) , 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 . It is structurally related to also from Agios.
(GtoPdb)
DESCRIPTION
Ivosidenib (AG-120) is an orally available inhibitor of isocitrate dehydrogenase type 1 (IDH1) with potential antineoplastic activity. It specifically inhibits a mutated form of IDH1 in the cytoplasm, preventing the formation of the oncometabolite 2-hydroxyglutarate (2 hG), which may induce cellular differentiation and inhibit cellular proliferation in IDH1-expressing tumor cells.
(TargetMol Bioactive Compound Library)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
2
Organisms
0
Compound Sets
21
Axon Medchem Screening Library
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
CZ-OPENSCREEN Bioactive Library
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
Guide to Pharmacology
Mcule NIBR MoA Box Subset
MedChem Express Bioactive Compound Library
NCATS Inxight Approved Drugs
NIH Approved Oncology Drugs
Novartis Chemogenetic Library (NIBR MoA Box)
ReFrame library
Selleckchem Bioactive Compound Library
TargetMol Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
25
Molecular Weight
582.14
Hydrogen Bond Acceptors
6
Hydrogen Bond Donors
1
Rotatable Bonds
7
Ring Count
5
Aromatic Ring Count
3
cLogP
4.32
TPSA
119.29
Fraction CSP3
0.29
Chiral centers
2.0
Largest ring
6.0
QED
0.44
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Member status
member
MOA
Inhibitor of mutant IDH1
Isocitrate Dehydrogenase inhibitor
Indication
acute myeloid leukemia (AML)
Target
IDH1
IDH1 inhibitor
Isocitrate Dehydrogenase (IDH)
Dehydrogenase
Pathway
Metabolism
Metabolic Enzyme/Protease
Therapeutic Class
Anticancer Agents
Source data
