NIK SMI1

Protein target name:

MAP3K14

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

~~100 nM~~

Reviewer suggested Concentration for use in cells:

150-400 nM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

STE

HUGO ID:

HGNC:6853

Entrez gene ID:

9020

UNIPROT ID:

Q99558

Target alias:

FTDCR1B, HS, HSNIK, NIK

Probe Details

Chemical Probes Portal ID:

CPP2067

Probe alias:

cpd 4f

PubChem CID:

117902000

ChEMBL ID:

CHEMBL4211840

SMILES string:

O=C(N)C1=NC(C2=CC=CC(C#C[C@]3(O)CCN(C)C3=O)=C2)=CC(OC)=C1

InChi Key:

LQSHXYHWYGKAMX-FQEVSTJZSA-N

PAINs evaluation:

PAINS-Free

Physico-chemical properties

Solubility - concentration:

139 uM

NMR:

1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.30(s, 1H), 7.68 (s, 1H), 7.57–7.56 (m, 3H), 3.98 (s, 3H), 3.41 (m, 2H), 2.83 (s, 3H), 2.52–2.50 (m, 1H), 2.30–2.21 (m, 1H).

13C NMR (101 MHz, DMSO) δ 171.28, 168.04, 166.31, 156.34, 152.68, 138.64, 132.97, 130.22, 129.53, 128.21, 122.78, 109.09, 107.48, 90.59, 84.35, 70.40, 56.37, 45.01, 36.54, 30.35.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.23 ± 0.17 nM

Potency assay:

NIK Ki biochemical assay

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

RelB 70 nM, RelA no inhibition, KHS1 > 50% in a 228 panel of kinases tested at 0.100 μM

In cell validation

On target activity in cells

Potency in cells:

IC50

34 ± 6 nM

Potency assay (cells):

NF-κB reporter assay; nuclear translocation inhibition of RelB

Off target activity in cells

Probe Selectivity in Cell:

Outside target family - Indirect: no inhibition of nuclear translocation of RelA

In vivo validation

Organism:

RatMouseDogMonkey

Dose:

5 mg/KgReviewer suggests higher than 100-200 mg/Kg PO

Route of delivery:

OralIntravenous

Plasma half life:

84.9/90.1/95.3 % (H/R/M)

Systemic clearance:

6.5/21/53/16/19 mL/min/Kg (H/R/M/D/C)

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.8b00678

Reference (PMID):

29940120

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

NIK SMI1:

Is a highly potent and selective NF-κB-inducing kinase (NIK) inhibitor with Ki of 0.23 nM for NIK-catalyzed hydrolysis of ATP to ADP.
Inhibits expression of NF-κB response element regulated firefly luciferase reporter gene in HEK293 cells at an IC50 of 34 nM.
has a favorable pharmacokinetic profile across species.
Inhibits BAFF-induced B cell survival in vitro (close to phenotype assay) at an IC50 of 373 nM.
Inhibits BAFF signalling and reduces splenic marginal zone B cells in mice at doses from 60-200 mg/kg.

Dec 8 2020 - 10:28am

The primary references provide strong support for on target NIK (MAP3K14) potency, efficacy and selectivity within the kinome for NIK SM1. In functional assays ~1 uM in cells and 200 mg/kg BID orally in C57BL/6 mice are recommended based on the data in the provided references. Selectivity profiling outside the kinome for safety pharmacology is not available and this unknown should modulate interpretation of in vivo results if readouts differ from the systems investigated in the references.

Mar 2 2021 - 1:58pm

NIK SMI1

Probe Availability

Probe Information

Target Details

FTDCR1B, HS, HSNIK, NIK

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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NIK SMI1

Probe Availability

Probe Information

Target Details

FTDCR1B, HS, HSNIK, NIK

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?