HG-9-91-01

Reagent Authentication Certificate:

Chemical Probes Portal HG-9-91-01.pdf

Protein target name:

SIK1, SIK2, SIK3

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

100-500 nM

Probe Availability

MedChem Express (1456858-58-4)

Cayman (1456858-58-4)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CAMK

HUGO ID:

HGNC:11142 HGNC:21680 HGNC:29165

Entrez gene ID:

150094 23235 23387

UNIPROT ID:

P57059 Q9H0K1 Q9Y2K2

Target alias:

Msk, Sik, Snf1lk

Probe Details

Chemical Probes Portal ID:

CPP98

Probe alias:

GTPL8049, CS-1749

PubChem CID:

78357808

SMILES string:

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

InChi Key:

UYUHRKLITDJEHB-UHFFFAOYSA-N

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 600 MHz (DMSO-d6) δ 11.54 (s, 1H), 9.19 (s, 1H), 8.38 (s, 1H), 7.29 (m, 2H), 7.15 (d, J = 9.0 Hz, 1H), 7.07 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 5.70 (s, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.05 (m, 4H), 2.44 (m, 4H), 2.23 (s, 6H), 2.22 (s, 3H)

13C NMR 125 MHz (DMSO-d6) δ 161.24, 160.34, 160.28, 156.51, 156.03, 152.59, 146.88, 135.46, 134.90, 131.38, 127.64, 125.99, 121.43, 120.62, 115.76, 105.42, 99.68, 55.75, 55.41, 48.57, 45.68, 18.30

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

SIK1 0.92 nM, SIK2, 6.6 nM, SIK3 9.6 nM

Potency assay:

In vitro kinase assay

Off target activity

Potency (off target):

IC50

Off target protein and potency:

NUAK2 145 nM

Potency assay (off target):

HG-9-91-01 was also active against SRC, LCK, YES, BTK, FGFRs, and Ephrin receptors. It was not active against any AMPK family kinases.

In cell validation

On target activity in cells

Potency assay (cells):

Inhibition of protein substrate phosphorylation in macrophages

Target engagement assay (cells):

Indirect: inhibition of protein substrate phosphorylation, and expression of a resistant mutant (SIK1 T96Q, gate-keeper mutation) rendered cells 100-1,000-fold less sensitive to HG-9-91-01.

Primary Reference

Reference (doi):

10.1073/pnas.1215450109

Reference (PMID):

23033494

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

In a limited panel (108 kinases), HG-9-91-01 inhibited several kinases (including SFKs) to a similar extent as the SIKs at 100 nM. Given the limited selectivity information available, use caution when using this probe.

Aug 29 2016 - 11:33pm

This probe is useful in cells when assayed alongside other, also not uniquely selective SIK inhibitors. Use in animals will require additional in vivo profiling (e.g., PK data).

Dec 26 2016 - 12:19pm

This compound showed several off-targets in a very limited kinase panel of 108 kinases with a concentration of 100 nM. To use this compound as a probe, more detailed selectivity data should be determined in order to avoid measuring off-target effects. As a pan-SIK inhibitor this compound is not appropriate to study the effects associated with a single isoform.

Feb 10 2017 - 1:45pm

HG-9-91-01

Probe Availability

Probe Information

Target Details

Msk, Sik, Snf1lk

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?

Search form

HG-9-91-01

Probe Availability

Probe Information

Target Details

Msk, Sik, Snf1lk

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?