ABBV-744

Protein target name:

BET BD2

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 100 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Bromodomain

HUGO ID:

HGNC:1103 HGNC:13575 HGNC:1104 HGNC:1105

Entrez gene ID:

6046 23476 8019 676

UNIPROT ID:

P25440 O60885 Q15059 Q58F21

Target alias:

BRD6, CT9, SPGF21, CAP, MCAP, HUNK1, HUNKI, BRD2-IT1, D6S113E, FSH, FSRG1, NAT, O27.1.1, RING3, RNF3, ORFX, RING3L

Probe Details

Chemical Probes Portal ID:

CPP1850

PubChem CID:

132010322

ChEMBL ID:

CHEMBL4297454

SMILES string:

CCNC(=O)C1=CC2=C(N1)C(=O)N(C=C2C3=C(C=CC(=C3)C(C)(C)O)OC4=C(C=C(C=C4C)F)C)C

InChi Key:

OEDSFMUSNZDJFD-UHFFFAOYSA-N

Physico-chemical properties

Solubility - preferred solvent:

DMSO

Solubility - concentration:

75 uM

NMR:

1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.31 (t, J = 5.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.33 – 7.25 (m, 2H), 6.94 (d, J = 9.1 Hz, 2H), 6.81 (s, 1H), 6.27 (d, J = 8.6 Hz, 1H), 4.95 (s, 1H), 3.57 (s, 3H), 3.23 (qt, J = 7.2, 5.3 Hz, 2H), 1.98 (s, 6H), 1.41 (s, 6H), 1.08 (t, J = 7.2 Hz, 2H).

13C NMR (101 MHz, DMSO-d6) δ 159.89, 159.07 (d, J = 240.6 Hz), 154.80, 153.15, 147.41 (d, J = 2.4 Hz), 144.30, 133.97, 133.28 (d, J = 8.9 Hz), 130.30, 129.91, 10 128.36, 125.62, 124.68, 124.27, 115.55 (d, J = 22.7 Hz), 112.37, 112.00, 106.19, 70.79, 36.31, 34.21, 32.44, 16.62, 16.61, 14.93.

Storage Recommendations

Storage (dry powder):

room temperature

Storage (solution):

-80°C, 6 months; -20°C, 1 month (stored under nitrogen)

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

2.1 nM BRD4 BD2,

Potency assay:

SPR of BRD4

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

6E6J, 6ONY

Structure-activity relationship:

yes see DOI:10.1038/s41586-020-1930-8

Off target activity

Potency assay (off target):

ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4, and more than 95× selectivity compared with BD1 of BRDt using TR-FRET.

Probe Selectivity in Vitro:

ABBV-744 lacked significant activity against 75 kinases and 22 bromodomain-containing proteins that represent diverse branches of the kinome and bromodome

In cell validation

On target activity in cells

Potency in cells:

IC50

11 nM (LNCaP), 9 nM (MDA-PCa-2B), 18 nM (MDV-R)

Potency assay (cells):

Cell proliferation assay

Off target activity in cells

Potency in cells, off target:

IC50

Off target protein and potency (cells):

BRD2 BD1 2449 nMBRD4 BD1 2006 nMBRDt BD1 1835 nMBRD3 BD3 7501 nM

Potency assay, off target (cells):

nanoBRET and TR-FRET

In vivo validation

Organism:

Mouse

Dose:

1 mg/kg

Route of delivery:

Oral

Plasma half life:

2.8 h

Fraction of probe bound to plasma protein:

58 %

Primary Reference

Reference (doi):

10.1038/s41586-020-1930-8 10.1021/acs.jmedchem.0c00628

Reference (PMID):

31969702 32324999

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

ABBV-744 is an excellent chemical probe for studies on the second bromodomain (BD2) of BET bromodomain proteins. The inhibitor is based on the panBET bromodomain inhibitor ABBV-075 (mivebresib) which I suggest to be used in parallel to study BD2 versus pan BET bromodomain selective effects. Unfortunately, no negative control has been used / characterized in the article by Faivre et al (Nature 578, 306-310). I recommend therefore using other available BET inhibitors of different scaffold in parallel in cell based studies. ABBV-744 is suitable for in vivo use in mice.

Jun 4 2020 - 3:27pm

ABBV-744

Probe Availability

Probe Information

Target Details

BRD6, CT9, SPGF21, CAP, MCAP, HUNK1, HUNKI, BRD2-IT1, D6S113E, FSH, FSRG1, NAT, O27.1.1, RING3, RNF3, ORFX, RING3L

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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ABBV-744

Probe Availability

Probe Information

Target Details

BRD6, CT9, SPGF21, CAP, MCAP, HUNK1, HUNKI, BRD2-IT1, D6S113E, FSH, FSRG1, NAT, O27.1.1, RING3, RNF3, ORFX, RING3L

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?