AGI-6780

Protein target name:

IDH2 R140Q

Mechanism of action:

Allosteric inhibitoruncompetitive with NADPHnoncompetitive with alphaKG substrate

Probe Availability

MedChem Express (1432660-47-3)

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Metabolic enzyme

Subclass:

Dehydrogenase

HUGO ID:

HGNC:5383

Entrez gene ID:

3418

UNIPROT ID:

P48735

Target alias:

Isocitrate dehydrogenase (NADP(+)) 2 mitochondrial, D2HGA2, ICD-M, IDH, IDHM, IDP, IDPM, mNADP-IDH

Probe Details

Chemical Probes Portal ID:

CPP1424

Probe alias:

AGI6780

PubChem CID:

71299339

ChEMBL ID:

CHEMBL3392845

SMILES string:

C1CC1NS(=O)(=O)C2=CC(=C(C=C2)C3=CSC=C3)NC(=O)NC4=CC=CC(=C4)C(F)(F)F

InChi Key:

CCAWRGNYALGPQH-UHFFFAOYSA-N

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

Kon

5.8 X 10^4 M min

Potency assay:

Koff=8.3 X 10^-3/min; IC50=23 nM in enzymatic assay

PDB ID for probe-target interaction (3D structure):

4JA8

Off target activity

Potency (off target):

IC50

Off target protein and potency:

IDH2 (WT): 190 nM, IDH1-R132H: 11,000 nM

Potency assay (off target):

In in vitro enzyme assays, IC50s>100,000 nM were measured for IDH1 (WT), LDHA, 3PGDH, GDH, and G6PDH.

In cell validation

On target activity in cells

Potency in cells:

EC50

11 nM

Potency assay (cells):

In U87 cells expressing the mutant protein, AGI-6780 dose-dependently decreased 2HG levels.

Target engagement assay (cells):

Indirect, inhibition of product formation.

Off target activity in cells

Potency in cells, off target:

EC50

Off target protein and potency (cells):

IDH1-R132H: >100,000 nM

Potency assay, off target (cells):

In U87 cells expressing the mutant protein, AGI-6780 was not very effective at decreasing 2HG levels.

Primary Reference

Reference (doi):

10.1126/science.1234769

Reference (PMID):

23558173

External Resources

Available data:

GDSC1 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-6780 currently represents the most appropriate probe molecule for the target; at the present time, the only literature (aside from the quoted 2013 Science paper) disclosing small-molecule inhibitors of the target are patents. The probe molecule should be used in the context of a relatively narrow published dataset, a specific caveat is that selectivity screening outside of a narrow range of closely related targets has not yet been reported.

Mar 28 2017 - 12:51pm

I would be very cautious with the interpretation of cellular data generated with this compound. It is a urea with three aromatic elements and no real solubilizing group. While I have no solubility data in aqueous medium to share, I would be very surprised if this compound had a solubility profile suitable for a reliable cellular testing. The molecule was tested in-house in one cell-based assay, arguably not an optimal assay, but little activity has been observed which may well be the result of poor solubility and/or permeability.

Mar 31 2017 - 7:53pm

AGI-6780

Probe Availability

Probe Information

Target Details

Isocitrate dehydrogenase (NADP(+)) 2 mitochondrial, D2HGA2, ICD-M, IDH, IDHM, IDP, IDPM, mNADP-IDH

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

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AGI-6780

Probe Availability

Probe Information

Target Details

Isocitrate dehydrogenase (NADP(+)) 2 mitochondrial, D2HGA2, ICD-M, IDH, IDHM, IDP, IDPM, mNADP-IDH

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?