I-BET151

Reagent Authentication Certificate:

Chemical Probes Portal I-BET151.pdf

Protein target name:

BRD2, BRD3, BRD4

Mechanism of action:

Antagonist

Recommended Concentration for use in cells:

250 nM - 1 uM

Probe Availability

Tocris (1300031-49-5)

MedChem Express (1300031-49-5)

MilliporeSigma (1300031-49-5)

Cayman (1300031-49-5)

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Bromodomain

HUGO ID:

HGNC:1103 HGNC:1104 HGNC:13575

Entrez gene ID:

6046 8019 23476

UNIPROT ID:

O60885 P25440 Q15059

Target alias:

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

Probe Details

Chemical Probes Portal ID:

CPP39

Probe alias:

GSK1210151A

PubChem CID:

52912189

ChEMBL ID:

CHEMBL2017291

SMILES string:

CC1=C(C(=NO1)C)C2=C(C=C3C(=C2)N=CC4=C3N(C(=O)N4)[C@H](C)C5=CC=CC=N5)OC

InChi Key:

VUVUVNZRUGEAHB-CYBMUJFWSA-N

Orthogonal probe:

MZP-54

PAINs evaluation:

PAINs free

Physico-chemical properties

Solubility - preferred solvent:

DMSO

Solubility - concentration:

20 mg/mL

NMR:

1H‐NMR (600 MHz, DMSO‐d6) δ ppm 2.03 (d, J=6.5 Hz, 3 H) 2.04 (s, 3 H) 2.25 (s, 3 H) 3.46 (bs, 3 H) 6.26 (q, J=7.1 Hz, 1 H) 6.69 (bs, 1 H) 7.35 (dd, J=7.0, 5.1 Hz, 1 H) 7.41 (d, J=6.6 Hz, 1 H) 7.76 ‐ 7.79 (m, 1 H) 7.79 (s, 1 H) 8.59 ‐ 8.65 (m, 2 H) 11.77 (bs, 1 H).

13C NMR (151 MHz, DMSO‐d6) δ ppm 10.26, 11.25, 17.63, 51.80, 55.4, 100.82, 112.01, 115.37, 120.20, 120.99, 122.69, 122.74, 128.08, 132.26, 132.78, 137.55, 139.77, 149.32, 154.26, 154.46, 158.99, 159.17, 165.96

Storage Recommendations

Storage (dry powder):

2 years -20 oC

Storage sensitivities:

Avoid freeze-thaw.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

BRD3 0.02 uM, BRD4 0.1 uM

Potency assay:

KD were measured IC50s were measured in ligand-displacement assays: BRD2 0.5 uM, BRD3 0.25 uM, BRD4 0.79 uM

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

3JVK

Off target activity

Probe Selectivity in Vitro:

At 10 uM, I-BET151 had minimal activity (<40%) against a broad panel of pharmacologically active receptors, with the most activity against TACR2.

In cell validation

On target activity in cells

Potency in cells:

IC50

0.16 uM

Potency assay (cells):

Inhibition of IL-6 production in PBMCs or whole blood (IC50 = 1.26 uM).

Target engagement assay (cells):

Proteomic interaction assays and ChIP assays In ChIP assays, I-BET151 led to a decrease in BRD3 and BRD4 recruitment to chromatin of target genes but not to housekeeping genes.

Off target activity in cells

Off target protein and potency (cells):

BRD9

Probe Selectivity in Cell:

In a proteomic selectivity profile assessing HL60 cell nuclear extracts, I-BET151 had no effect on 23 off-target bromodomains other than BRD9.

In vivo validation

Organism:

Balb/c mice

Dose:

3 mg/mL

Route of delivery:

Intravenous

Other route of delivery:

oral

Plasma half life:

1.8 h (IV), 2.6 h (oral)

Systemic clearance:

8 mL/min/kg (IV)

Cmax:

83.9 uM (IV), 3.87 (oral)

Tmax:

1.02 h (oral)

Primary Reference

Reference (doi):

10.1038/nature10509

Reference (PMID):

21964340

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

Due to the low potency of I-BET151, I would not recommend it as a cellular probe. More potent probes for BRD4 exist (e.g., JQ1 and I-BET762). None of these are selective for BRD4 though; they inhibit all of the BET family proteins with equal potency.

Jun 12 2016 - 1:40pm

In a single-dose, mouse PK study (IP administration), I-BET-151 showed increased exposure and half-life compared to JQ1.

Jun 12 2016 - 1:41pm

There are a number of well-characterized tool molecules available for the BRD2/3/4 family, and anyone seeking to use one of these probes is advised to consult the Chemical Probes Portal pages to view the latest molecules and data before selecting the appropriate probe. Across the probes listed, JQ1, PFI-1 as well as this I-BET151 are all broadly selective for the sub-family of BRD4-related bromodomains, with some evidence of cellular and in vivo activity. The relative levels of potency/activity are different across these assays. This molecule (like JQ1) is very well characterized, with wide selectivity building confidence that this probe will act on the BRD4-related bromodomains rather than on other targets.

Sep 8 2016 - 4:18pm

I-BET151 is less potent than other BET inhibitors such as JQ1, but it has better in vivo PK properties in mice.

Apr 27 2017 - 9:46pm

I-BET151

Probe Availability

Probe Information

Target Details

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

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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I-BET151

Probe Availability

Probe Information

Target Details

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

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?