THZ1

Covalent Inhibitor of CDK7

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

CDK7

Covalent Inhibitor

10 nM - 1 uM

DOI - 10.1038/nature13393

Probe Availability:

In Vitro Validations

Uniprot ID: P50613

Target Class: Kinase

Target SubClass: CMGC

Potency: Kd

Potency Value: 3.2 nM

Potency Assay: Time-dependent binding established supporting covalent mechanism

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

Target aliases:

Cyclin-dependent kinase 7, STK1, MO15, CDKN7, CAK1 ...

DOI Reference: 10.1038/nature13393

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay, off target (cells): KiNativ profiling against 246 kinases in Loucy cells was performed showing >75% inhibition at 1 uM of: MLK3, PIP4K2C, JNK1, JNK2, JNK3, MER, TBK1, IGF1R, NEK9, PCTAIRE2, and TBK1, but in vitro binding to off-target kinases was not time dependent indicating that inhibition was not via a covalent mechanism.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Kinativ analysis indicates ~9 kinases other than CDK7 are inhibited by 1000 nM THZ1 at >75%. In Loucy cells, although only CDK7 experienced time-dependent inhibition suggestive of covalent binding.

(last updated: 20 May 2016 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

THZ1 is a useful first-generation probe for assessing CDK7 (with some activity towards CDK12/13) in cells and in mice. For in vivo use, THZ1 has some challenges due to poor solubility and limited stability. In cell and in vivo target engagement can be confirmed by immunoblotting for reduction in phosphorylation levels of the C-terminal domain of RNAPII at Ser 2, 5 and 7.

(last updated: 31 May 2016 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

THZ-1 is a useful first-generation probe for cellular studies involving CDK7. Although not perfectly selective (~ 8 other kinases are inhibited at 1 uM in the Kinativ analysis covering about half of the kinome). Ideally, results obtained with THZ-1 would be verified by using another CDK7 inhibitor, although no perfect probe is available yet. The control compound THZ1-R should also be used in parallel to further validate the results.

(last updated: 6 Sept 2016 )

SERP Comments:

(last updated: 6 Sept 2016 )

Portal Comments

In 2019, Browne M. et al employed a chemoproteomic approach (CITe-Id), revealing the dose-dependent competitive binding of THZ1 to eight protein targets, at concentration exceeding 350 nM. Among the established targets were CDKs 7, 12, and 13. Beyond these confirmed findings, the study unveiled unexpected dose-dependent THZ1 competitive binding to several kinase targets, including PKN3, PRKCQ, and GSK3B. DOI: 10.1021/jacs.8b07911

(last updated: 21 Nov 2023)