AGI-6780

AGI-6780 : Allosteric inhibitor of IDH2, uncompetitive with NADPH, noncompetitive with alphaKG substrate

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(1 ratings)

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Information

IDH2 (R140Q)

Allosteric inhibitor, uncompetitive with NADPH, noncompetitive with alphaKG substrate

Probe Availability:

In Vitro Validations

Uniprot ID: P48735

Target Class: Other

Target SubClass: Dehydrogenase

Potency: IC 50

Potency Value: 23 nM R140Q

Potency Assay: Enzymatic assay

PDB ID for probe-target interaction (3D structure): 4JA8

Target aliases:

Isocitrate dehydrogenase [NADP], mitochondrial, ID ...

DOI Reference: 10.1126/science.1234769

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency end-point : IC50 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.

Potency in cells, off target : EC50 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.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP 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.

(last updated: 28 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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.

(last updated: 31 Mar 2017 )

SERP Ratings

In Cell Rating

(last updated: 9 Apr 2017 )