WM-1119

HAT inhibitor of KAT6A

Structure

Information

Protein target names: KAT6A

Mechanism of action: HAT inhibitor

Primary References:

In Vitro Validations

Uniprot ID: Q92794
Target Class: Other
Target SubClass: Lysine Acetyltransferase
Potency: IC50, KD
Potency Value: 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
Target aliases:
Histone acetyltransferase KAT6A, ZNF220, RUNXBP2, ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP 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.

(last updated: 28 Aug 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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

(last updated: 24 Sept 2020 )