WH-4-023

Protein target name:

LCK, SRC

Mechanism of action:

Inhibitor

Probe Availability

MedChem Express (837422-57-8)

Tocris (837422-57-8)

MilliporeSigma (837422-57-8)

Cayman (837422-57-8)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:6524 HGNC:11283

Entrez gene ID:

3932 6714

UNIPROT ID:

P06239 P12931

Target alias:

IMD22, LSK, YT16, p56lck, pp58lck

Probe Details

Chemical Probes Portal ID:

CPP77

Probe alias:

GTPL8068, KIN112

PubChem CID:

11844351

ChEMBL ID:

CHEMBL213100

SMILES string:

CC1=C(C(=CC=C1)C)OC(=O)N(C2=C(C=C(C=C2)OC)OC)C3=NC(=NC=C3)NC4=CC=C(C=C4)N5CCN(CC5)C

InChi Key:

NBTNHSGBRGTFJS-UHFFFAOYSA-N

Orthogonal probe:

A-770041

PAINs evaluation:

Yes, but note that this is recognized as a PAIN by virtue of a p-aminotertiary aniline group and the PAINS moeity responsible is touted as an alphascreen-selective interence moeity, not a general promiscuity moiety

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO-d6) ä ppm 1.78-1.88 (m, 2 H), 2.093 (s, 6 H), 2.24 (s, 3 H), 2.36- 2.47 (m, 6 H), 2.50 (m, 4 H), 3.65 (s, 3 H), 3.76 (s, 3 H), 3.83- 3.91 (m, 5 H), 6.40 (s, 1 H), 6.68 (dd, J ) 8.59, 2.53 Hz, 1 H), 6.76 (m, 1 H), 6.80 (d, J ) 2.53 Hz, 1 H), 6.84-6.92 (m, 1 H), 7.01-7.14 (m, 3 H), 7.34 (d, J ) 8.59 Hz, 1 H), 7.43 (d, J ) 5.81 Hz, 1 H), 8.35 (d, J ) 5.81 Hz, 1 H), 9.22 (s, 1 H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

LCK 0.6 nM, SRC 1 nM

Off target activity

Potency (off target):

IC50

Off target protein and potency:

BTK 0.1 uMFGFR10.11 uMJAK2 0.24 uMKDR 0.14 uMp38 alpha 0.53 uMSYK 0.2 uMTIE2 0.2 uMZAP70 0.37 uM

In cell validation

On target activity in cells

Potency in cells:

IC50

61 nM

Potency assay (cells):

Inhibition of IL-2 secretion

Target engagement assay (cells):

Indirect: inhibition of substrate phosphorylation

In vivo validation

Organism:

Sprague-Dawley rat

Dose:

5 mg/kg

Route of delivery:

Oral

Fraction of probe bound to plasma protein:

0.98

Cmax:

22 ng/mL

Tmax:

4 hr

Organ of Interest

Organ (O):

T cell

Primary Reference

Reference (doi):

10.1021/jm060435i

Reference (PMID):

16884310

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

5 review(s)

Rating for use in Model Organisms

5 review(s)

SAB Members

SAB Comments

Poor bioavailability hampers use of WH-4-023 as in vivo probe in mice.

Jun 30 2016 - 3:40am

This appears to be non-selective versus Src. Further kinase profiling is needed prior to recommendation as a probe for Lck.

Jun 30 2016 - 4:49am

WH-4-023 is compound 28 in the referenced work. However, this compound is one of a number synthesised, and the actual paper discusses detailed profiling of a compound 43. This later compound is more potent in cells, is better characterised in terms of its kinase selectivity, and has in vivo data presented (PK and PD). It is not clear how compound 28 has received the designation of WH-4-023 in preference to the true subject of the paper (Compound 43). In the absence of any detailed profiling of 28 it cannot be recommended as a suitable probe. This is also not a recommendation of compound 43 - that should be considered separately. Both compounds, and the series in general would appear to be potent pan SRC/LCK-family inhibitors, and possess a number of other activities, including a range of sub uM kinase activities not always associated with SRC-family inhibition. Much more selective probes for LCK exist, see for example A-770041 from Abbott.

Jun 30 2016 - 4:50am

This is a very promiscuous tyrosine kinase inhibitor.

Jun 30 2016 - 4:50am

WH-4-023

Probe Availability

Probe Information

Target Details

IMD22, LSK, YT16, p56lck, pp58lck

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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WH-4-023

Probe Availability

Probe Information

Target Details

IMD22, LSK, YT16, p56lck, pp58lck

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?