SGC-CK2-1

Protein target name:

CSNK2A1, CSNK2A2

Mechanism of action:

Inhibitor, ATP competitive

Recommended Concentration for use in cells:

up to 500 nM

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CMGC

HUGO ID:

HGNC:2457 HGNC:2459

Entrez gene ID:

1457 1459

UNIPROT ID:

P68400 P19784

Target alias:

CK2; CKII; Cka1; Cka2; CK2A1; OCNDS; CK2A2, CK2alpha', CSNK2A1

Probe Details

Chemical Probes Portal ID:

CPP2206

Probe alias:

cpd 24, QBE

PubChem CID:

146681133

SMILES string:

CC1=CC=C(NC2=NC3=C(C#N)C=NN3C(NC4CC4)=C2)C=C1NC(CC)=O

InChi Key:

YKDZIFFKQUNVHH-UHFFFAOYSA-N

Control compound:

SGC-CK2-1N

Orthogonal probe:

CX-4945

Physico-chemical properties

NMR:

1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.21 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.01 (s, 1H), 2.59 (m, 1H), 2.34 (q, J = 7.5 Hz, 2H), 2.16 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H), 0.80 (m, 2H), 0.72 (m, 2H);

13C NMR (176 MHz, DMSO-d6) δ 172.1, 157.1, 151.0, 148.4, 145.2, 138.2, 136.7, 130.4, 125.5, 116.6 (2C), 115.0, 76.4, 76.2, 29.2, 23.4, 17.3, 10.2, 6.6 (2C); H

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

4.2 nM CK2α @ 10µM ATP, 2.3 nM CK2α' @ 10µM ATP

Potency assay:

Enzymatic Assay (Eurofin)

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

6Z83

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

SGC-CK2-1 was profiled in the KINOMEscan assay against 403 wild-type kinases at 1 μM. Only 11 kinases showed PoC <35 giving an S(35) at 1 μM = 0.027. Potential off-targets were tested in the nanoBRET target engagement assay (DYRK2) or via Eurofins radiometric and LANCE kinase assays and found to be at least 100 fold weaker.

In cell validation

On target activity in cells

Potency in cells:

IC50

36 nM CK2α, 16 nM CK2α’

Potency assay (cells):

NanoBRET

Off target activity in cells

Probe Selectivity in Cell:

SGC-CK2-1 was profiled against 140 cancer cell lines in eight-point dose-response. It inhibited cell proliferation below 500 nM in one cell line, a pro-monocytic, human histiocytic lymphoma line U-937. Profiled using NCI60 panel at 10 uM, SGC-CK2-1 elicited minor lethality (8%–22%) in A498, HS 578T, RXF 393, and SNB-75 cells.

Primary Reference

Reference (doi):

10.1016/j.chembiol.2020.12.013

Reference (PMID):

33484635

External Resources

Available data:

SGC Chemical Probes

Under Review

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

Part of SGC Chemical Probe Collection

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

no rating

SAB Members

SAB Comments

There is a disconnect in the linked publication between the NanoBret cellular IC50 of 16-36 nM and the apparent functional IC50 of inhibiting AKT S129 phosphorylation that appears to be ~500 nM. It is unclear then if the lack of activity as an antiproliferative for which CK2 inhibitors have been claimed as a result of weaker cellular activity than NanoBret estimates or off-target pharmacology of previous tools as the authors suggest. Consistent with this concern, the previously reported enzymatic potency (presumably measured near the Km of ATP) of compounds 16 and 29 are near equipotent with the in-cell NanoBret potencies reported here, which is unlikely in that multimillimolar ATP in cells surely competes with an ATP-competitive ligand. Finally, it is unclear if the reported compound (24) is truly more selective than the previously reported compound 22, which by NanoBret is an order of magnitude more potent. Selectivity based on the % of kinases inhibited by a threshold amount at a fixed concentration will always favor the weaker compound.

May 20 2021 - 12:37pm

SGC-CK2-1 is a valuable probe for interrogating the cellular effects of CK2 inhibition, as it is considerably more selective against related kinases such as DYRK2 than previously reported inhibitors of this kinase including CX-4945. In addition to having excellent cellular and biochemical activity, SGC-CK2-1 has a structurally related negative control available that helps further support target validation. SGC-CK2-1 is active in two orthogonal cellular assays, cellular inhibition of pAKT and nanobret target engagement assay. Although its selectivity over other kinases is excellent, it is of similar potency against CK2a and CK2a’. It appears to have excellent cellular penetration based on its published target engagement data and anti-proliferative activities in one cell line. Although it possesses modest biochemical activity against DYRK2, it has no activity against DYRK2 in the nanobret assay. The pharmacokinetics and ADME properties of SGC-CK2-1 have not yet been interrogated, so no in vivo target validation/activity studies are advised until further profiling has been done.

May 20 2021 - 12:39pm

SGC-CK2-1

Probe Information

Target Details

CK2; CKII; Cka1; Cka2; CK2A1; OCNDS; CK2A2, CK2alpha', CSNK2A1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

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SGC-CK2-1

Probe Information

Target Details

CK2; CKII; Cka1; Cka2; CK2A1; OCNDS; CK2A2, CK2alpha', CSNK2A1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?