AT1

Degrader (PROTAC) of BRD4

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(1 ratings)

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Information

Protein target names: BRD4

Mechanism of action: Degrader (PROTAC)

Recommended in-cell concentration:

100-1000 nM

Primary References:

DOI - 10.1038/nchembio.2329

Probe Availability:

In Vitro Validations

Uniprot ID: O60885

Target Class: Epigenetic

Target SubClass: Bromodomain

Potency: Kd

Potency Value: 75 nM BD1, 45 nM BD2

Potency Assay: Isothermal Titration Calorimetry ITC

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

Structure-activity relationship: SAR available as described in Gadd et al. Nat Chem Biol. doi:10.1038/nchembio.2329 AT2 (butyl), AT3 (PEG2), AT4 (poly-propyleneglycol-2), AT5 (mixed PEG-alkyl chain linker) and AT6 (PEG3) were all evaluated for their selectivity of intracellular degradation against BRD4 vs BRD2 vs BRD3. AT1 has a linear hexyl chain linker

Target aliases:

Bromodomain-containing protein 4, HUNK1, BRD4, BRD ...

DOI Reference: 10.1038/nchembio.2329

In Cell Validations

In Vivo Data

No in Vivo Validations

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

(last updated: 15 Apr 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

AT1 is a very good PROTAC ligand for targeted degradation of BRD4. Improved from previous PROTAC MZ1, AT1 has superior selectivity towards BRD4 in the BET family while retaining its potency (DC50 = 100nM). The paper has provided ample evidence detailing that selectivity is achieved via ligand-induced protein-protein interaction (PPI) between BRD4 and VHL. AT1 is thus structurally optimized from MZ1 to facilitate PPI. However, the ITC measurements do not fully explained AT1’s superior selectivity. More data is also needed for the probe’s use in organisms (e.g. PK and toxicity studies).

(last updated: 15 May 2020 )

SERP Ratings

In Cell Rating

SERP Comments:

AT-1 is the first selective BRD4 PROTAC with in-family selectivity over BRD2 and BRD3. We have used it successfully in comparative studies with pan-BET PROTACs in different cell lines. Based on our experience, it is worth titrating the concentration of AT-1 if a new cell line is used for the first time, as there is a certain cell-type variability (as with most if not all PROTACs).

(last updated: 14 Dec 2020 )