TP-472

TP-472 : Inhibitor of BRD9, BRD7

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(0 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 TP-472 is in the process of SERP review.

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Information

BRD9
BRD7

Inhibitor

up to 1 uM

Additional Data

SGC Chemical Probe Collection

Probe Availability:

In Vitro Validations

Uniprot ID: Q9H8M2

Target Class: Epigenetic

Target SubClass: Bromodomain

Potency: ΔTm

Potency Value: 9.9 °C

Potency Assay: DSF

PDB ID for probe-target interaction (3D structure): 6V1U, 6V14, 6Y7L, 6V16

Target aliases:

Bromodomain-containing protein 9, BRD9, BRD9_HUMAN ...

DOI Reference: 10.1021/acs.jmedchem.9b01980

Uniprot ID: Q9H8M2

Target Class: Epigenetic

Target SubClass: Bromodomain

Potency: Kd

Potency Value: 82 nM

Potency Assay: ITC

PDB ID for probe-target interaction (3D structure): 6V1U, 6V14, 6Y7L, 6V16

Target aliases:

Bromodomain-containing protein 9, BRD9, BRD9_HUMAN ...

DOI Reference: 10.1021/acs.jmedchem.9b01980

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

No binding to any BRD in a panel of >40 BRD in thermal shift assay with exception of BRD7 and BRD9. TP-472 and TP-472N were screened in the Eurofins CEREP Diversity Profile to measure binding to a range of Receptors, Ion Channels and enzymes @10 uM. The Inhibition as the mean % of control is shown below, results showing an inhibition or stimulation lower than 50% are considered to represent significant effects. TP-472 showed binding to Adenosine A1 receptor (14%), Benzodiazepine receptor (47%), PDE2A1 (h) (25%), PDE3A (h) (48%) and PDE4D2 (h) (28%). TP-472N showed binding to A1 receptor (35%), A3 receptor (23%), Melatonin receptor MT1 (47%) and Cl- channel (GABA-gated) (20%).

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

This probe shows reasonable on-target potency against BRD9 (33nM by ITC, 368nM in HEK293 cells by NanoBRET) and a very clean selectivity profile, with BRD7 (340nM by ITC) the only significant off-target noted. It shows improved selectivity vs CECR2 compared to alternative probe BI-9564. As multiple probes are available, I recommend using TP-472 alongside not only its negative control but also BI-9564 and i-BRD9 (which shows improved selectivity vs BRD7). In addition to the NanoBRET activity, TP-472 shows good PAMPA permeability (data provided by SGC), suggesting cellular access is not likely to be an issue, although no transporter data is provided. Cytotoxicity is not observed up to 100uM. Although the probe is not proposed for in vivo use, low dose PK data suggests this may be feasible - further PK studies including assessment of free compound levels are required to further understand potential for in vivo use.

(last updated: 22 Nov 2022 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

The probe characterisation would benefit from cytotoxicity assessment. No publications are available so far (for in-cell data and target engagement) but these can be found on the SGC website.

(last updated: 22 Mar 2023 )

Portal Comments

In a 2023 study, Hu et al. evaluated TP-472 in live-cell assays for Phospholipidosis induction, cautioning about adverse effects at concentrations near 1 uM. (DOI:10.1016/j.chembiol.2023.09.003)

(last updated: 7 Nov 2023)