AMG-18

Allosteric inhibitor of ERN1

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(1 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

ERN1

Allosteric inhibitor

100 - 1,000 nM

DOI - 10.1021/ml500315b

Probe Availability:

In Vitro Validations

Uniprot ID: O75460

Target Class: Kinase

Target SubClass: Other

Potency: IC50

Potency Value: 13 nM

Potency Assay: IRE 1 biochemical fluorescence quenching kinase assay: A truncated human IRE1α WT protein, containing the catalytic part (AA 469-977), was expressed in insect cells. The purified protein (1.2 μg/mL) was incubated with a fluorescently quenched IRE1α substrate (1.45 μg/mL; 5’ [6FAM] – GAG UCC GCA GCA CUC - [BHQ1] 3’) and a titration of inhibitor, starting at 50 μM (final DMSO concentration = 1%), for 40 min at room temperature in assay buffer. Reactions were carried out in a final volume of 20 μL in a 384 well PP plate (Greiner #784209). The reaction was stopped by addition of 15 μL 100 mM Tris-HCl pH9 and the fluorescence intensity of the IRE1α-substrate was measured using a fluorescent plate reader (Ex 485 nm / Em 535 nm, Perkin Elmer Envision).

PDB ID for probe-target interaction (3D structure): 4U6R

Structure-activity relationship: Described based on biochemical and cellular data in ACS Med. Chem. Lett. 2015, 6, 68−72

Target aliases:

Serine/threonine-protein kinase/endoribonuclease I ...

DOI Reference: 10.1021/ml500315b

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency end-point : IC50 JNK3 2.5 uM

Potency assay (off target): Kinase selectivity panel (DiscoveRX KINOMEscan): all 100 kinases < 50% at 1 uM; AMG-18 is 192-fold selective for IRE1 over JNK3.

Probe Selectivity in Vitro:

Not available

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 16 Jan 2017 )

SERP Ratings

In Cell Rating

(last updated: 8 Apr 2017 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

The compound was only tested against 100 kinases and additional testing against a larger panel of kinases would be desirable to ensure selectivity.

(last updated: 23 Sept 2024 )