AGI-5198

Protein target name:

IDH1 R132H

Mechanism of action:

Inhibitor

Probe Availability

MedChem Express (1355326-35-0)

MilliporeSigma (1355326-35-0)

Cayman (1355326-35-0)

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Metabolic enzyme

Subclass:

Dehydrogenase

HUGO ID:

HGNC:5382

Entrez gene ID:

3417

UNIPROT ID:

O75874

Target alias:

HEL-216, HEL-S-26, IDCD, IDH, IDP, IDPC, PICD

Probe Details

Chemical Probes Portal ID:

CPP152

Probe alias:

1355326-35-0, AGI-5198(IDH C35)

PubChem CID:

56645356

ChEMBL ID:

CHEMBL2180727

SMILES string:

CC1=CC=CC=C1C(C(=O)NC2CCCCC2)N(C3=CC(=CC=C3)F)C(=O)CN4C=CN=C4C

InChi Key:

FNYGWXSATBUBER-UHFFFAOYSA-N

Orthogonal probe:

GSK864

PAINs evaluation:

PAINs free

Physico-chemical properties

Storage Recommendations

Storage (solution):

-20 oC 2 years

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

70 nM

Potency assay:

NADPH consumption

Off target activity

Potency (off target):

IC50

Off target protein and potency:

wild-type IDH1 >100 uMIDH2 isoforms >100 uM

Potency assay (off target):

NADPH consumption

In cell validation

On target activity in cells

Potency assay (cells):

In TS603, TS676, and TS516 glioma cells, AGI-5198 showed a dose-dependent impact on R-2HG formation

Target engagement assay (cells):

Indirect assay, R-2HG formation

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

None detected up to 20 uM

In vivo validation

Organism:

mice

Dose:

150 mg/kg, 450 mg/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

Indirect: quantification of R-2HG

Primary Reference

Reference (doi):

10.1126/science.1236062

Reference (PMID):

23558169

External Resources

Available data:

GDSC2

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

AGI-5168 was the prototypical IDH-1 R132H inhibitor but in time has been surpassed in potency and characterization by the later compound GSK864, which also offers an inactive control for proof of target involvement. However, as a second, distinct chemotype this probe may offer some utility for confirmation of phenotypes in cellular assays.

Jun 11 2016 - 4:22am

AGI-5198 is a potent, selective inhibitor of IDH1 R132H and R132C mutants [in vitro IC50 R132H IDH1 = 0.07 µM and IC50 R132C IDH1 = 0.16 µM, respectively]. The compound is totally selective against wild-type IDH1, wild-type IDH2 or IDH2 mutants (IC50s > 100 μM). Compared in a R132H-IDH1 glioma xenografts, AGI-5198 (450 mg/kg/day) caused 50-60% growth inhibition over a treatment period of three weeks (no sign of toxicity during 3 weeks daily treatment). AGI-5198 did not affect the growth of IDH1 wild-type glioma xenograph. In the U87 R132H tumor xenograft mouse model, AGI-5198 shows ∼90% tumor 2-HG inhibition in vivo following three twice daily doses (150 mg/kg).

Aug 29 2016 - 3:11pm

AGI-5198 has been superseded in biochemical and cellular potency by GSK864 and is recommended mainly for use as a mutant IDH1 inhibitor from a distinct chemical class for confirmatory studies in cells. Characterization of off-target activities in cells would be helpful to support use of this compound. AGI-5198 requires high doses for in vivo activity, but the oral dosing route may be of use, compared to GSK864 which is recommended for intraperitoneal dosing.

Apr 12 2017 - 12:51pm

AGI-5198

Probe Availability

Probe Information

Target Details

HEL-216, HEL-S-26, IDCD, IDH, IDP, IDPC, PICD

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?

Search form

AGI-5198

Probe Availability

Probe Information

Target Details

HEL-216, HEL-S-26, IDCD, IDH, IDP, IDPC, PICD

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?