THAL-SNS-032

Protein target name:

CDK9, CDK10

Mechanism of action:

DegraderPROTAC

Recommended Concentration for use in cells:

~~250 nM to 5 uM~~

Reviewer suggested Concentration for use in cells:

250 - 1000 nM

Probe Availability

MedChemExpress

TOCRIS

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CMGC

HUGO ID:

HGNC:1780 HGNC:1770

Entrez gene ID:

1025 8558

UNIPROT ID:

P50750 Q15131

Target alias:

TAK; C-2k; CTK1; CDC2L4; PITALRE; ALSAS; PISSLRE

Probe Details

Chemical Probes Portal ID:

CPP2072

Probe alias:

cpd 2, PROTAC

PubChem CID:

131801483

ChEMBL ID:

CHEMBL4587232

SMILES string:

CC(C)(C1=CN=C(O1)CSC2=CN=C(S2)NC(C3CCN(CC3)CC(NCCOCCOCCOCCNC4=C5C(N(C(C5=CC=C4)=O)C6CCC(NC6=O)=O)=O)=O)=O)C

InChi Key:

BXDZOYLPNAIDOC-UHFFFAOYSA-N

Orthogonal probe:

NVP-2

Validation in Cells and Model Organisms

In vitro validation

On target activity

Structure-activity relationship:

In cell validation

On target activity in cells

Potency in cells:

EC50

50 nM

Potency assay (cells):

Western Blot

Target engagement assay (cells):

Within Target Family: >15-fold selectivity for Cdk9 over other CDKs (EC50 values are 62, 171 and 398 nM for Cdk2, Cdk1 and Cdk7). Outside Target Family: THAL-SNS-032 exhibited potent inhibition of proliferation across a panel of eleven different leukemia cancer cell lines.

Phenotypic Control Experiment:

CDK9 degradation was blunted by pre-treating MOLT4 cells with the proteasome inhibitor MG132, indicating that CDK9 degradation requires an active proteasome. Pre-treatment with excess thalidomide or SNS-032, was able to block CDK9 degradation, which is consistent with a requirement for engagement of both CRBN and CDK9 in the same complex to achieve CDK9 degradation.

Primary Reference

Reference (doi):

10.1038/nchembio.2538

Reference (PMID):

29251720

External Resources

Available data:

Nathanael Gray Lab - Probe Collection

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

no rating

SAB Members

SAB Comments

This probe is a degrader version of the inhibitor NVP-2. Both probes inhibit additional kinases in vitro, but the probe here selectively degrades CDK9 (and CDK10). Best use would be comparison of the effects due to loss of CDK9 (and CDK10) versus inhibition of these kinases. Probe has been used in the MOLT4 cell line, use of this probe in additional cell lines would need initial validation of the degradation efficiency.

Mar 19 2021 - 12:22pm

A potential and selective PROTAC molecule to degrade cellular level of CDK9. Very fast degradation kinetics was observed. Good evidence of UPS mediated degradation using CRBN negative cell line control. DC50 of this particular probe was not determined and the relevant concentration to effectively degrade CDK9 can be lower. Global degradation selectivity might be different as short time point (2h) was used in the MS experiment.

Mar 29 2021 - 9:36pm

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