CPI-637

Protein target name:

CREBBP, EP300

Mechanism of action:

Antagonist

Recommended Concentration for use in cells:

up to 10 uM

Probe Availability

MedChem Express (1884712-47-3)

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Bromodomain

HUGO ID:

HGNC:2348 HGNC:3373

Entrez gene ID:

1387 2033

UNIPROT ID:

Q09472 Q92793

Target alias:

CREB binding protein, CBP, KAT3A, RSTS, RSTS1, E1A binding protein p300, KAT3B, RSTS2, p300

Probe Details

Chemical Probes Portal ID:

CPP1319

PubChem CID:

121271792

SMILES string:

C[C@@H]1CC(=O)NC2=CC=CC(=C2N1)C3=CC4=C(C=C3)N(N=C4C5=CN(N=C5)C)C

InChi Key:

BFTKDWYIRJGJCA-CYBMUJFWSA-N

Control compound:

enant-CPI-637: S)-4-methyl-6-(1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one

Physico-chemical properties

NMR:

1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1 H), 7.93 - 7.89 (m, 1H), 7.83 - 7.81 (m, 1H), 7.53 - 7.49 (m, 1H), 7.43 - 7.39 (m, 1H), 7.13 - 7.07 (m, 1H), 7.01 - 6.92 (m, 2H), 4.15 (s, 3H), 4.01 (s, 3H), 3.99 - 3.96 (m, 1H), 2.82 - 2.75 (m, 1H), 2.51 - 2.45 (m, 1H), 1.19 (d, J = 6.27 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 171.71, 139.95, 137.01, 136.90, 136.49, 133.80, 130.60, 128.42, 127.48, 127.25, 127.05, 121.53, 120.99, 120.84, 120.32, 114.69, 109.18, 54.51, 40.36, 38.62, 35.06, 23.06.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

CBP: 0.03 uM

Potency assay:

Isothermal calorimetry assay. In TR-FRET assays, CPI-637 had IC50 CBP=0.03 uM and EP300=0.051 uM.

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

5I8G

Structure-activity relationship:

Yes, see ACS Med Chem Lett paper

Off target activity

Potency (off target):

IC50

Off target protein and potency:

BRD9: 0.73 uM, BRD4: 11 uM

Potency assay (off target):

In TR-FRET assays, CPI-637 was at least 700-fold selective for the targets over other Bromodomain proteins.

In cell validation

On target activity in cells

Potency in cells:

EC50

CBP: 0.3 uM

Potency assay (cells):

NanoBRET assay (Promega) in transfected HEK293 cells. In AMO-1 cells, CPI-637 inhibited MYC expression with an EC50=0.6 uM.

Target engagement assay (cells):

Yes, nanoBRET assay.

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.6b00075

Reference (PMID):

27190605

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

no rating

SAB Members

SAB 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.

Apr 27 2017 - 11:48am

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.

May 15 2017 - 11:34am

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.

Nov 17 2020 - 7:52pm

CPI-637

Probe Availability

Probe Information

Target Details

CREB binding protein, CBP, KAT3A, RSTS, RSTS1, E1A binding protein p300, KAT3B, RSTS2, p300

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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CPI-637

Probe Availability

Probe Information

Target Details

CREB binding protein, CBP, KAT3A, RSTS, RSTS1, E1A binding protein p300, KAT3B, RSTS2, p300

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?