KI-696

Protein target name:

KEAP1

Mechanism of action:

Inhibitor of KEAP1-NRF2 protein-protein interaction

Recommended Concentration for use in cells:

Up to 1 uM

Probe Information

Target and Probe Information

Target Details

Target class:

Kelch-like ECH associated protein 1, INrf2, KLHL19

Probe Details

Chemical Probes Portal ID:

CPP1574

Probe alias:

L6I

PubChem CID:

118170767

ChEMBL ID:

CHEMBL3819587

SMILES string:

C(C[C@@H](C1=CC=C(C(=C1)CN3[S](C2=CC=CC=C2O[C@@H](C3)C)(=O)=O)C)C4=CC(=C5C(=C4)N=N[N]5C)OC)(=O)O[H]

InChi Key:

ZDNGJXBUEQNFBQ-GCJKJVERSA-N

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

1.3 nM

Potency assay:

Isothermal Calorimetry (ITC)

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

5fnu

Off target activity

Probe Selectivity in Vitro:

OATP1B1 binding assay IC50 - 2.5 uM;
Bile salt export pump - IC50 - 4.0 uM;
PDE3A binding assay - IC50 - 10 uM

In cell validation

On target activity in cells

Potency in cells:

EC50

12 nM

Potency assay (cells):

Beas2B cells treated with compound and NQO1 activity measured after 48 hrs using MTT. NQO1 is an NRF2-dependent gene.

Target engagement assay (cells):

Normal Human Bronchial Epithelial (NHBE) cells transfected with Nrf2 siRNA showed loss of NQO1 and GCLM mRNA expression and NQO1 activity. NQO1 and GCLM are NRF2-dependent genes.

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

>10 uM in Beas2B cells

In vivo validation

Organism:

Han Wistar Rat

Dose:

35-50 µmol/kg

Route of delivery:

Intravenous

Plasma half life:

1.6 h

Systemic clearance:

70 mL/min/kg

Cmax:

655 ng/mL (IV)84 ng/mL (Oral)

Organ of Interest

Organ (O):

Lung

Target engagement assay:

KI-696 induces gene expression of NRF2-dependent genes (e.g., Nqo1, HO-1, Txnrd1, Srxn1, Gsta3, Gclc) in the lung.

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.6b00228

Reference (PMID):

27031670

Endorsed probe

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

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

KI-696 represents an excellent LMW tool to study the KEAP1-NRF2 interaction in vivo. Discovered by FBS, the probe is well characterised in a number of in vitro assays as well as showing robust in vivo effects. The in vivo application is hampered by low bioavailability and high clearance, necessitating IV infusions as the mode of administration, which may limit the usefulness of the probe in vivo.

Jun 23 2017 - 11:49am

Given the labile sulfoxide-N bond, this is likely to be a covalent inhibitor.

Aug 7 2017 - 4:04pm

This compound has high selectivity and works in low nanomolar range in cells. Thus, it should be a good tool for cell-based interrogations. In vivo, it has pharmacokinetic issues such as short half-life, high clearance and lack of oral bioavailability. Having these limitations at hand, it can still be used for in vivo usage upon IV injection at the indicated doses.

Nov 16 2020 - 8:53pm

KI-696

Probe Information

Target Details

Kelch-like ECH associated protein 1, INrf2, KLHL19

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

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KI-696

Probe Information

Target Details

Kelch-like ECH associated protein 1, INrf2, KLHL19

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?