A-196

A-196 : Substrate-competitive, SAM non-competitive inhibitor of KMT5B, KMT5C

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

KMT5B
KMT5C

Substrate-competitive inhibitor, SAM non-competitive inhibitor

Probe Availability:

MedChem Express (A-196)

In Vitro Validations

Uniprot ID: Q4FZB7

Target Class: Epigenetic

Target SubClass: Protein methyltransferase

Potency: IC 50

Potency Value: 25 nM

Potency Assay: Scintillation proximity assay - Methyltransferase activity assays for SUV420H1 and SUV420H2 were performed by monitoring the incorporation of tritium-labeled methyl group to monomethylated lysine 20 of peptide H4(1-24) (H4K20Me1). The experiments were performed in triplicate.

PDB ID for probe-target interaction (3D structure): 5CPR

Structure-activity relationship: Yes, to be published separately

Target aliases:

Histone-lysine N-methyltransferase KMT5B, SUV420H1 ...

DOI Reference: 10.1038/nchembio.2282

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency end-point : IC50

Potency assay (off target): Scintillation proximity assay. No activity was detected in assays with 29 methyltransferases at 1 or 10 uM. No activity was detected against other epigenetic proteins (chromatin binders and readers, including 53BP1 and WDR5).

Probe Selectivity in Vitro:

125 non-family targets including kinases, GPCRs, ion channels, and transporters (via Cerep and the PDSP panels) were screened. Significant inhibition was observed at 10 uM for six of these targets: Adenosine receptors A1 (Ki=0.021 uM), A2 (Ki=0.028 uM), A3 (Ki=2 uM), GABA-gated chloride channel (Ki=1.8 uM), NK2 (Ki=4.1 uM), DOP (Ki=9 uM).

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SERP ratings and comments

SERP Ratings

In Cell Rating

(last updated: 15 Mar 2017 )

SERP Ratings

In Cell Rating

(last updated: 21 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

This probe represents the best in class for SUV420H1 and H2 - hitting the enzymes at 25 and 144 nM, respectively, with selectivity data against a wide panel of related epigenetic and other targets. The originating paper gives good confidence around this molecule and includes strong biochemical, biophysical, structural & cellular data, as well as structurally related negative controls. No data are presented for the wider pharmacokinetic, drug-like profiles, and so no conclusion can be drawn on its suitability as a probe for use in model organism studies. However, permeability from cellular studies and chemical structure would support its further investigation towards these studies.

(last updated: 30 Mar 2017 )