A1H7Z

A1H7Z : Inhibitor of NSD2

Structure

SERP Rating

In Cells

(2 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.

Probe A1H7Z is in the process of SERP review.

Please continue to check back for new reviews and commentary.

Information

NSD2 (Other variant:PWWP1 domain)

Inhibitor

up to 1 uM

In Vitro Validations

Uniprot ID: O96028

Target Class: Epigenetic

Target SubClass: Methyltransferase

Potency: IC50

Potency Value: 6.3 nM

Potency Assay: NSD2 biophysical binding

PDB ID for probe-target interaction (3D structure): 9EXY

Target aliases:

Histone-lysine N-methyltransferase NSD2, WHSC1, TR ...

DOI Reference: 10.1021/acs.jmedchem.4c00215

Uniprot ID: O96028

Target Class: Epigenetic

Target SubClass: Methyltransferase

Potency: Kd

Potency Value: 2.5 nM

Potency Assay: SPR

PDB ID for probe-target interaction (3D structure): 9EXY

Target aliases:

Histone-lysine N-methyltransferase NSD2, WHSC1, TR ...

DOI Reference: 10.1021/acs.jmedchem.4c00215

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Selective against within family (NSD3 SPR Kd pIC50 4.6)

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

A1H7Z (Cpd 34) is a biochemically potent ligand for the PWWP1 domain of NSD2 with selectivity over NSD3. It is demonstrated to bind to the NSD2-PWWP1 pocket in cell based (NanoBRET luciferase) assays but did not reduce cellular H3K36Me2 (this being regulated by the NSD2 SET domain). In vivo characterisation in rats was limited to single dose PK studies which indicated low oral bioavailability and high blood clearance.

(last updated: 5 Aug 2024 )

SERP Ratings

In Cell Rating

SERP Comments:

The selectivity of this compound is not adequately evaluated, neither globally nor in a sufficiently complete panel of PWWPs. As a result, the data presented is inadequate to qualify it as a probe for in cell use. The intravenous half-life is not ideal. The clearance is too fast and may be problematic for model organism use. There is also insufficient data for in vivo target engagement or drug on-target effects.

(last updated: 17 Aug 2024 )