THAL-SNS-032

Protein target name:

CDK9, CDK10

Mechanism of action:

DegraderPROTAC

Recommended Concentration for use in cells:

250 nM to 5 uM

Probe Availability

MedChemExpress

TOCRIS

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

cyclin dependent kinase

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

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

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