CPI-637 : Antagonist of EP300, CREBBP



Protein target names: EP300, CREBBP

Mechanism of action: Antagonist

Recommended in-cell concentration:
up to 10 uM

In Vitro Validations

Uniprot ID: Q09472
Target Class: Epigenetic
Target SubClass: Bromodomain
Potency: IC 50
Potency Value: 51 nM
Potency Assay: TR-FRET assay
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: Yes, see ACS Med Chem Lett paper
Target aliases:
Histone acetyltransferase p300, P300, EP300, EP300 ...

DOI Reference: 10.1021/acsmedchemlett.6b00075

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

SERP Comments:

CPI-637 is a potent dual inhibitor of CBP (30 nM) and EP300 (51 nM) as measured by TR-FRET platform assays. CPI-637 is active in cells and inhibits MYC expression in AMO-1 cells with an EC50=600 nM. However, CPI-637 also has activity at BRD4(1) (11,000 nM; 360-fold) and BRD9 (730 nM; 24-fold) which seems insufficient considering the dominance of the BET phenotype. Furthermore, it is asserted that "BRD9 bromodomain has not been shown to produce a pronounced cellular phenotype (data not shown)." This data needs to be shown and peer reviewed to justify this statement and minimize the risk of low selectivity of BRD9. Affinity for BRD9 can also be accompanied with affinity for BRD7, which has not been evaluated. CPI-637 has only been cross-screened in 9 other BRDs, and no data is disclosed that addresses general pharmacology (i.e., non-BRD proteins). These screens are readily accessible so I believe CPI-637 has been insufficiently characterized for use as a chemical probe. More supporting data are required.

(last updated: 27 Apr 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

This is a high quality probe that is appropriate for interrogating CBP/EP300 cell biology in certain circumstances. CPI-637 is structurally differentiated from other CBP/EP300 chemical probes, and thus adds value to the bromodomain chemical probe toolbox. The enantiomer is also reported, which is substantially weaker and may, therefore, be of use as a negative control. I disagree with the comment (Taylor et al, ACS Med Chem Lett 2016) that BRD9 potency is 'acceptable' as this will be context-dependent, depending on how the probe is used. Inhibition of MYC expression by the probe is not a direct measure of CBP/EP300 target engagement. The limited off-target profiling (both within the bromodomain family and beyond) is a weakness of this probe - broader off-target profiling is recommended.

(last updated: 15 May 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

This is a high quality compound originating from a dedicated medicinal chemistry effort to arrive at a molecule with 30/51 nM IC50 against CBP/EP300 in TR-FRET assays that causes cellular phenotypes below 1 uM. Selectivity over the BRD4 BD1 is >700-fold, however the compound also inhibits the bromodomain of BRD9 in biochemical assays at concentrations below 1 uM. A limitation in the characterization of this compound is that in total it has only been profiled against 15 bromodomains and no information is available on off-targets in cellular assays.  

(last updated: 17 Nov 2020 )