WM-1119

Protein target name:

KAT6A

Mechanism of action:

HAT inhibitor

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

TOCRIS

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

HAT

Subclass:

Lysine Acetyltransferase

HUGO symbol:

HGNC:13013

Entrez gene ID:

7994

Target alias:

MOZ; ARTHS; MRD32; MYST3; MYST-3; ZNF220; RUNXBP2; ZC2HC6A

Probe Details

Chemical Probes Portal ID:

CPP1837

Probe alias:

WM 1119, Compound-4

PubChem CID:

133080719

SMILES string:

C1=CC=C(C(=C1)F)S(=O)(=O)NNC(=O)C2=CC(=CC(=C2)C3=CC=CC=N3)F

InChi Key:

QLXULUNLCRKWRD-UHFFFAOYSA-N

Control compound:

Compound 187Compound 188Compound 189

Physico-chemical properties

Solubility - concentration:

25-50 ug/ml

NMR:

1H NMR (400 MHz, DMSO-d6) δ = 10.98 (brs, 1H), 10.43 (brs, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.31 (s, 1H), 8.13–8.02 (m, 2H), 7.96 (t, J = 7.7 Hz, 1H), 7.82 (t, J = 7.3 Hz, 1H), 7.70 (dd, J = 12.7, 7.3 Hz, 1H), 7.54 (d, J = 9.8 Hz, 1H), 7.43 (dd, J = 17.4, 7.9 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50, KD

6.3 nM IC50, 2 nM KD

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

6CT2

Structure-activity relationship:

yes, see DOI: 10.1021/acs.jmedchem.9b02071

Off target activity

Probe Selectivity in Vitro:

WM-1119 is 1,100-fold and 250-fold more active against KAT6A than against KAT5 or KAT7

In cell validation

On target activity in cells

Potency in cells:

IC50

0.250 uM

Potency assay (cells):

Cell cycle analysis, Western

Target engagement assay (cells):

> 1 µM G1 cell cycle arrest

Off target activity in cells

Probe Selectivity in Cell:

No affinity on off-target panel of 159 diverse targets at 1 or 10 µM

In vivo validation

Organism:

Rat

Dose:

2.9 (IV) mg/kg33 (PO) mg/kg

Route of delivery:

IntravenousOral

Plasma half life:

7.7 h (IV), 6.4 h (PO)

Systemic clearance:

21 mL/min/kg

Cmax:

2.9 uM

Tmax:

1 h

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.9b02071 10.1038/s41586-018-0387-5

Reference (PMID):

32118427 30069049

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

This probe has been developed by a strong medicinal chemistry approach for which more than 180 analogs have been profiled in in vitro KAT6A activity assays (Priebbenow J Med Chem 2020). WM-1119 is a highly potent KAT6A inhibitor with high selectivity over KAT5 and KAT7. A crystal structure confirms the binding mode as an acetyl-CoA competitive inhibitor. No detailed SAR data compared to KAT6B have been reported, but the authors state that limited testing suggests these compounds behaves as dual KAT6A/B inhibitor. The compound has further been profiled against a panel of 159 targets where no other affinities have been detected. However, no general methods like interaction proteomics or thermal proteome profiling for comprehensively identifying interactors have been identified. Considering that the compound acts as a competitive inhibitor of acetyl-CoA, it will be important to profile whether other acetyl-CoA binders are also interacting with WM-1119.

Cellular data reported for this compound rely on the measurement of indirect effects like growth inhibition and expression changes, whereas direct measurement of acetylation changes has only been reported for the analog WM-8014.

Detailed characterization of physicochemical and pharmacological parameters including solubility, plasma protein binding, microsome stability and permeability and plasma concentrations after IV and oral dosing in rat and IP dosing in mice are available.

Aug 28 2020 - 8:03am

I agree with the recommended oral dose in rats, however I do not recommend dosing rats intravenously with WM-1119. In mice, I recommend dosing intraperitoneally at 50mg/kg

Sep 24 2020 - 11:42am

WM-1119

Probe Availability

Probe Information

Target Details

MOZ; ARTHS; MRD32; MYST3; MYST-3; ZNF220; RUNXBP2; ZC2HC6A

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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WM-1119

Probe Availability

Probe Information

Target Details

MOZ; ARTHS; MRD32; MYST3; MYST-3; ZNF220; RUNXBP2; ZC2HC6A

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?