AG-270

Allosteric Inhibitor of MAT2A

Structure

Information

Protein target names: MAT2A

Mechanism of action: Allosteric Inhibitor

Recommended in-cell concentration:
up to 1 uM
Primary References:

In Vitro Validations

Uniprot ID: P31153
Target Class: Other post-translational modification
Target SubClass: Methionine Adenosyltransferase
Potency: IC50
Potency Value: 14 nM
Potency Assay: Enzymatic MAT2A inhibition assay
PDB ID for probe-target interaction (3D structure): 7KCC
Structure-activity relationship: yes
Target aliases:
S-adenosylmethionine synthase isoform type-2, MATA ...

DOI Reference: 10.1021/acs.jmedchem.0c01895

Uniprot ID: P31153
Target Class: Other post-translational modification
Target SubClass: Methionine Adenosyltransferase
Potency: % in
Potency Value: 91 %
Potency Assay: Enzymatic MAT2A inhibition assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
S-adenosylmethionine synthase isoform type-2, MATA ...

DOI Reference: 10.1021/acs.jmedchem.0c01895

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

Comments:

AG-270 is a well-characterised tool compound for the study of allosteric MAT2A inhibition both in cells and in vivo mouse models at the recommended concentration and dose ranges. However, AG-270 has low aqueous solubility (< 1.0 uM at pH 7.4) and required a spray-dried dispersion formulation for oral pharmacokinetic studies in higher species. Oral dosing in mouse models bearing human tumour xenografts utilised a bespoke formulation (6.7 % w/w HPMCAS-MF, 1% w/w PVP K30, 2% w/w TPGS, 0.1% Simethicone) – see J. Med Chem. 2021, 64, 4430-4449 Supplementary Information. Thus, care is required in the formulation of AG-270 to ensure adequate exposure in both cell-based and especially in vivo studies.

(last updated: 21 Jun 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

The compound is poorly soluble thus special care must be taken when preparing formulations for in vivo work. Specifically, the compound must be prepared as a spray-dried dispersion.

(last updated: 25 Jun 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

AG-270 was developed from a relatively weak binder and abundant SAR data and co-crystal structures with its intended target MAT2A, demonstrate the inhibition mechanism. Cellular and in vivo effects make sense with the expected phenotypes and it appears there are no obvious off-target effects in cellular assays. Negative control compounds for AG-270 exist. Proteome-wide selectivity has not yet been demonstrated by using MAT2A resistance alleles, however, this is a minor concern since collectively all the available data suggests that AG-270 is a potent and selective inhibitor of MAT2A.

(last updated: 7 Jul 2021 )